The earliest mention of Prescot in any surviving record appears in the Pipe Roll of 1178, when the rector had incurred a fine of one mark (13s. 4d.) for some offence against forest law. Much of Lancashire was then "afforested", and the Master Forester of Lancaster in the thirteenth century held as one of the manors of his "Forest Fee" that of Whiston, to which the advowson of Prescot rectory was appurtenant. It is probable (hat Prescot manor had been carved from Whiston (which originally included Eccleston also), as an endowment for the rectory; hence the rector was lord of the manor.

In the Middle Ages Prescot parish covered fifty-eight square miles, and comprised no fewer than fifteen townships, namely Eccleston, Parr, Prescot, Rainford, Rainhill, Sutton, Whiston, Windle, Bold, Cronton, Cuerdley, Ditton, Penketh, Sankey and Widnes. From about 1200 the seven last-named of these townships were provided with a chapel of ease at Farnworth in Widnes, and became known as "Farnworth side". Subsequently, at uncertain dates, pre-Reformation chapels were erected at Rainford and Windle: from the latter, dedicated to St. Helen, the modern town of St. Helens derives its name. A chantry chapel, of which ruins remain, was built at Windleshaw in the fifteenth century and a chapel of ease was built at Sankey shortly before 1650. The parish, however, remained intact until the nineteenth century.

The town of Prescot grew up near the church, where an informal Sunday market became established. (This was not finally abolished until 1587.) In 1333, William de Dacre, rector and lord of the manor, received licence to establish a weekly market on Mondays and an annual fair of three days at Corpus Christi. Shortly afterwards the place was probably made a seignorial borough, as its holdings were later styled "burgages". The Monday market of 1333 and a Friday market granted in 1458 did not long survive, but the Tuesday market established in 1587 and the Corpus Christi fair, lasted until modern times.

That Prescot was of some importance in the medieval period is shown by its inclusion on the fourteenth-century Bodleian map of Britain. The advowson of the rectory was acquired in 1391 by John of Gaunt, Duke of Lancaster, from whom it passed to his descendants, the Lancastrian kings. It was bestowed by King Henry VI upon his new foundation of King's College. Cambridge, in 1445, and two years later the rectory was formally appropriated by the college. The rectory had by this date become very wealthy; a legend tells of a rector whose horse was shod with silver. After 1447 no more individual rectors were presented, a vicarage being created instead. The vicarage house, first built in 1458, was rebuilt about 1722 and was again rebuilt in 1956. The profits of the rectory (the "great tithes") were farmed out by the college to Lord Stanley and his descendants. Earls of Derby, from 1457 until 1642, during which time the earls were stewards of Prescot Manor.

Prescot records are abundant from the sixteenth century onwards, there being court rolls from 1510, Churchwarden’s accounts from 1523 (the earliest in Lancashire), and parish registers from 1573. Leland in 1540 described it as "a little market, having no notable water about it". The Grammar School (which still flourishes) was founded by Gilbert Lathum, Archdeacon of Man in 1544. The progress of the town was facilitated by its situation on the main highway from Liverpool to Warrington and Wigan. The presence of mineral wealth encouraged industries, coalmining and earthenware manufacture being recorded in Elizabethan limes. The earliest recorded colliery railway in England existed here in 1594. The copyholders gained the unique right of mining under their copyholds without any licence, restriction or payment. A playhouse was built here probably at the instance of William, sixth Earl of Derby, prior to 1600, but did not long survive.

In 1610 the parish church, which had for long been "ruinous", was taken down and rebuilt, except for the north vestry, which is probably fifteenth-century. It is notable for a fine open timber nave roof. Interesting Jacobean stalls with misericords were added in 1636, the elegant tower and spire in 1729 and enlarged aisles in 1981''.

The failure of this enterprise in 1912 was a great disaster for the town. The old watch factory is now a great printing and bookbinding works. The principal industry, however, is the manufacture of cables.