After a period of local rule, Mathura was conquered by the Indo-Scythians during the first century BCE. The Indo-Scythian satraps of Mathura are sometimes called the "Northern Satraps", as opposed to the "Western Satraps" ruling in Gujarat and Malwa. However, Indo-Scythian control proved to be short lived, following the reign of the Indo-Scythian Mahakshatrapa ("Great Satrap") Rajuvula, c. 10–25 CE. The Mora Well inscription of Mahakshatrapa Rajuvula, of the early decades of the first century CE, found in a village seven miles from Mathura, stated that images pratima(h) of the blessed (bhagavatam) five Vrishni heroes, were installed in a stone shrine of a person called Tosa.^[21] The heroes were identified from a passage in the Vayu Purana as Samkarsana, Vasudev, Pradyumna, Samba, and Aniruddha.^[22] The English translation of the inscription read:-

. . . of the son of mahakṣatrapa Rāṃjūvula, svāmi . . . The images of the holy paṃcavīras of the Vṛṣṇis is... the stone shrine... whom the magnificent matchless stone house of Toṣā was erected and maintained... five objects of adoration made of stone, radiant, as it were with highest beauty...^[23]

The Mathura inscription of the time of Mahakshatrapa Rajuvula's son, Mahakshatrapa Sodasa recorded erection of a torana (gateway), vedika (terrace) and chatuhsala (quadrangle) at the Mahasthana (great place) of Bhagavat Vasudeva.^[24] Several male torsos representing the Vrisni heroes were also found in a shrine in Mora dating to the time of Mahakshatrapa Sodasa.^[21]

The Kushan emperors took control of Mathura some time after the Mahakshatrapa ("Great Satrap") Sodasa (reigned circa 15 CE), although several of his successors ruled as Kushan vassals, such as the Indo-Scythian Mahakshatrapa Kharapallana and the Satrap Vanaspara, both of whom paid allegiance to the Kushans, in an inscription at Sarnath, dating to the third year of the reign of the Kushan emperor Kanishka the Great c. 130 CE.^[25]

The Kushans made Mathura one of their capitals. (Preceding and/or concurrent capitals of the Kushans included Kapisa [modern Bagram, Afghanistan], Purushapura [modern Peshawar, Pakistan] and Takshasila [adjoining modern Taxila, Pakistan].)

Mathuran art and culture reached its zenith during the Kushan era.^[26] Perhaps the most famous example was the artistic style known as the Mathura school. Mathura ateliers were most active during the epoch of the great Kushan emperors Kanishka, Huvishka, Vasudeva whose reign represents the Golden Age of Mathura sculpture.^[27]

During the 3rd century CE, following the decline of the Kushan Empire, the Naga dynasty of Padmavati took control of Mathura.^[28]

In the reign of Chandragupta Vikramaditya, a magnificent temple of Vishnu was built at the site of Katra Keshavadeva.^[27] Kalidasa, hailed as the greatest poet and dramatist in Sanskrit, in the fourth-fifth century CE mentioned the groves of Vrindavan and Govardhan hill as:

...the king of Mathura, whose fame was acknowledged in song even by the devatas... At that moment, though still in Mathura, it appears as if Ganga has merged with Yamuna at the Sangam... In a Vrindavan garden which is superior even to Kubera's garden, known as Chaitra-ratha... You can, as well, during rains, look at the dancing peacocks, while sitting in a pleasant cave of the Goverdhan Mountain.^[29]

Chinese Buddhist Monk Faxian mentions the city as a centre of Buddhism about 400 CE. He found the people were very well off, there were no taxes other than for those on farmers who tilled the royal land. He found that people did not kill animals, no one consumed wine, and did not eat onion or garlic. He found that engraved title deeds were issued to land owners. Visiting priests were provided with accommodation, beds, mats, food, drinks and clothes to perform scholarly works.^{[30][page needed]}

Xuanzang, who visited the city in 634 CE, mentions it as Mot'ulo, recording that it contained twenty Buddhist monasteries and many Hindu temples.^[31][32] Later, he went east to Thanesar, Jalandhar in the eastern Punjab, before climbing up to visit predominantly Theravada monasteries in the Kulu valley and turning southward again to Bairat and then Mathura, on the Yamuna river.^[33]

The famous female Alvar saint, Andal visualised going to a pilgrimage which began at Mathura, then proceeded to Gokul, the Yamuna, the pool of Kaliya, Vrindavan, Govardhan, and finished at Dwarka.^[34] The eleventh century Kashmiri poet, Bilhana visited Mathura and Vrindavan after leaving Kashmir en route to Karnataka.^[35]

The city was sacked and many of its temples destroyed by Mahmud of Ghazni in 1018 CE.^[32] The capture of Mathura by Maḥmūd Ibn Sebüktegīn is described by the historian al-Utbi (Abu Nasr Muhammad ibn Muhammad al Jabbaru-l 'Utbi) in his work Tarikh Yamini as follows:

The wall of the city was constructed of hard stone, and two gates opened upon the river flowing under the city, which were erected upon strong and lofty foundations, to protect them against the floods of the river and rains. On both sides of the city there were a thousand houses, to which idol temples were attached, all strengthened from top to bottom by rivets of iron, and all made of masonry work; and opposite to them were other buildings, supported on broad wooden pillars, to give them strength.

In the middle of the city there was a temple larger and firmer than the rest, which can neither be described nor painted. The Sultan thus wrote respecting it :— " If any should wish to construct a building equal to this, he would not be able to do it without expending an hundred thousand thousand red dinars, and it would occupy two hundred years, even though the most experienced and able workmen were employed." Among the idols there were five made of red gold, each five yards high, fixed in the air without support. In the eyes of one of these idols there were two rubies, of such value, that if any one were to sell such as are like them, he would obtain fifty thousand dinars. On another, there was a sapphire purer than water, and more sparkling than crystal; the weight was four hundred and fifty miskals. The two feet of another idol weighed four thousand four hundred miskals, and the entire quantity of gold yielded by the bodies of these idols, was ninety-eight thousand three hundred miskals. The idols of silver amounted to two hundred, but they could not be weighed without breaking them to pieces and putting them into scales. The Sultan gave orders that all the temples should be burnt with naphtha and fire, and levelled with the ground.^[36]

The temple at Katra was sacked by Maḥmūd Ibn Sebüktegīn. A temple was built to replace it in 1150 CE. The Mathura prasasti (Eulogistic Inscription) dated Samvat (V.S.) 1207 (1150 CE), said to have been found in 1889 CE at the Keshava mound by Anton Fuhrer, German Indologist who worked with the Archaeological Survey of India, recorded the foundations of a temple dedicated to Vishnu at the Katra site:

Jajja, who carried the burden of the varga, together with a committee of trustees (goshtijana), built a large temple of Vishnu, brilliantly white and touching the clouds.

Jajja was a vassal of the Gahadavalas in charge of Mathura, and the committee mentioned in the prasasti could have been of an earlier Vaishnava temple.^[37] The temple built by Jajja at Katra was destroyed by the forces of Qutubuddin Aibak, though Feroz Tughlaq (r. 1351–88 CE) was also said to have attacked it.^[38] It was repaired and survived till the reign of Sikandar Lodi (r. 1489–1517 CE).

In the twelfth century, Bhatta Lakshmidhara, chief minister of the Gahadavala king Govindachandra (r. 1114–1155 CE), wrote the earliest surviving collection of verses in praise of the sacred sites of Mathura in his work Krtyakalpataru, which has been described as "the first re-statement of the theory of Tirtha-yatra (pilgrimage)".^[39] In his Krtyakalpataru, Bhatta Lakshmidhara devoted an entire section (9) to Mathura.^[40]

Later on the city was sacked again by Sikandar Lodi, who ruled the Sultanate of Delhi from 1489 to 1517 CE.^[41][42] Sikandar Lodi earned the epithet of 'Butt Shikan', the 'Destroyer of Idols'. Ferishta recorded that Sikandar Lodi was a staunch Muslim, with a passion for vandalising Hindu temples:

He was firmly attached to the Mahomedan religion, and made a point of destroying all Hindu temples. In the city of Mathura he caused masjids and bazaars to be built opposite the bathing-stairs leading to the river, and ordered that no Hindus should be allowed to bathe there. He forbade the barbers to shave the beards and heads of the inhabitants, in order to prevent the Hindus following their usual practices at such pilgrimages.^[43]

In Tarikh-i Daudi, of 'Abdu-lla (written during the time of Jahangir) said of Sikandar Lodi:

He was so zealous a Musulman that he utterly destroyed divers places of worship of the infidels, and left not a vestige remaining of them. He entirely ruined the shrines of Mathura, the mine of heathenism, and turned their principal Hindu places of worship into caravanserais and colleges. Their stone images were given to the butchers to serve them as meat-weights, and all the Hindus in Mathura were strictly prohibited from shaving their heads and beards, and performing their ablutions. He thus put an end to all the idolatrous rites of the infidels there; and no Hindu, if he wished to have his head or beard shaved, could get a barber to do it. Every city thus conformed as he desired to the customs of Islam.^[44]

Vallabhacharya and Chaitanya Mahaprabhu arrived in the Braj region, in search of sacred places that had been destroyed or lost. In Shrikrsnashrayah, that make up the Sodashagrantha, Vallabha said of his age:

The Malechchhas (non-Hindus in this context) have surrounded all the holy places with the result that they have become infected with evil. Besides, the holy people are full of sorrow. At such a time Krishna alone is my way.

During the period of the expansion of Maratha Empire, pilgrimage to the holy places in the north became quite frequent. Pilgrims required protection on the way and took advantage of the constant movement of troops that journeyed to and back from their homeland for military purposes. That is how the practice arose of ladies accompanying military expeditions. The mother of Peshwa Balaji Baji Rao, Kashitai performed her famous pilgrimage for four years in the north, visiting Mathura, Prayag, Ayodhya, Banaras, and other holy places.^[55]