A settlement existed in the Penryn area before the Norman conquest. In the Domesday survey of 1086 Penryn is part of the Manor of Treliwel. Around 1100 the parishes of Mabe, Gluvias, Mylor, and Budock were reserved to the Bishop. It is said the town was founded in 1216 by Bishop Simon of Exeter. The town's Episcopal Charter of incorporation dates from 1236 and was confirmed in 1275 when it was obtained by the bishops of Exeter, lords of the local manor. The remainder of the Manor was known as the Manor of Penryn Foreign. A Royal Charter of 1259 granted the borough a market, a fair, and a free warren. The charter granted a market weekly on Mondays, but by one means or other Penryn established a market on Saturday and on other days. The grant of the market carried with it the right to establish a Court of Pye Powder. This court decided minor matters of commercial and other disputes during the holding of the market. By the grant of the market, Penryn also legally became a port. They had the right of appointing a Portreeve who was the chief officer of the trading town.
It was the founding of the Collegiate Church of Glasney in 1265 that gave Penryn its importance. Penryn became a great seat of ecclesiastical learning for three centuries. In 1311, Kind Edward II granted to the Bishop of Exeter a fair at Penryn.
Before the construction of the forts at St. Mawes and on Pendennis head at the mouth of the Fal in the sixteenth century the estuary was open to attack by French and Spanish ships prowling off Cornish coast. A boom was placed across the entrance to block the ships.
The dissolution of Glasney College occurred in 1548. In 1549, the manor of Penryn town and borough was held by Sir Humphrey Arundell. He led the Cornish Rebellion of 1549 with the support of a number of the leading Penryn burgess. The rebels were defeated and Arundell was executed in London.
After London, during the Tutor period Penryn saw more shipping than any other port on the south coast of England. A majority of ships made it a port of call on outbound voyages and the first port of call on inbound voyages. In 1308, Penryn had four active flour mills a very large number for so small a manor. In 1327, half of the population of Penryn were foreigners (probably mostly from Brittany). At least three Penryn mayors were convicted of piracy between 1550 and 1650. Prior to the 19th century Penryn mainly earned a living from the sea. Granite had been shipped from the harbour for centuries. Penryn had two smelting houses for tin in 1697 for export to London. The town or exchequer quay was built between 1676 and 1703. It was the intention to prevent landing of goods at numerous places to make the work of the custom officers too difficult. The ownership of the Penryn harbours was to the See of Exeter. In 1875, the ownership of Penryn harbour was conveyed to the Corporation of Penryn. In 1757, Richard Williams employed 600 people in a factory for the manufacture of "woolens".
Penryn borough was incorporated by Royal Charter in 1621. The Penryn government included a mayor, aldermen, assistants, two constables, a recorder, and two sergeants-at-mace.
Extremely hard times were experienced in Penryn in the middle of the 19th century. Many persons were forced to leave Cornwall, particularly the miners, to seek employment in other countries. Mr. Davy of Helston Road advanced money for men to go abroad, particularly to South Africa. By the beginning of the Second World War a majority of the men worked on the Falmouth docks.