The Collegiate Church was completed in Manchester in the early 16th Century, today showcasing the original carved choir stalls. The Earl of Derby built a chapel on occasion of his safe return from the Flodden Field battle against the Scots in 1513. The cathedral was re-established as a Protestant institution after the Reformation in England. Dr John Dee, an eminent physician, was a warden there. 

Manchester was a prosperous market town in the 16th Century because of its textile industry. The weaving of fustian, a variety of heavy cotton fabrics, began in 1620, which ensured additional impetus to the town's growth. The textile industry continued to develop rapidly through the 17th Century, in part due to contacts with London City, eventually resulting in Manchester's stronghold of Puritanism, which took the side of Parliament in the religious dispute against Charles I. Many historians believe that the first civil war in England actually broke out in Manchester in 1642, with its first casualty claiming the life of a weaver named Richard Percival.
   
The actions of Lord Strange, the son of the Earl of Derby, ultimately resulted in Percival's bitter death. After this, Strange fled, only to return some years later to attempt an unsuccessful campaign to lay siege to the town. When the monarchy was re-established in 1660, Manchester faced harsh punishment for having supported Parliament, and was deprived of representation in Parliament until 1832.
 
After the civil wars, Humphrey Chetham bought the former college buildings. They became known as Chetham's Hospital, and later, Chetham's School of Music. Chetham endowed the institution with a book collection, which became the first free public library in Britain, still open today.

The Glorious, or Bloodless Revolution occurred in 1688, when James II was overthrown by a parliamentary union, with the support of Dutch governor William of Orange. The revolutionaries had Manchester's unwavering support. The city's residents were dissatisfied with the Tory clergymen in the church and Lady Ann Bland founded the new St Ann's Church, consecrated in 1712, which epitomises early Georgian architecture. In 1745, the pretender Charles Stuart invaded Manchester with his army. The city offered feeble resistance and the Jacobeans established the so-called Manchester Regiment, which proved to be short-lived and soon surrendered to the British Army.