Matthew Brown was born in the White Deer Valley of Northumberland County, Pennsylvania, where his father had removed from Carlisle to become one of the earliest settlers in the area.  The father, an elder in the Reformed Presbyterian Church, was an active opponent of colonial rule; he died of fever while serving in the Revolutionary War.  The two year old Matthew was taken in by an uncle, William Brown, who lived near Harrisburg.  As a prominent figure in Dauphin County, Brown was able to provide his adopted son with an education in local schools before enrolling him in Dickinson College in nearby Carlisle, Pennsylvania.  Graduating with the class of 1794, Matthew returned to Northumberland County where he began to teach classical school; his intellectual pursuits brought him into contact with such noted individuals as Joseph Priestley.  He also began to study divinity in 1796 and three years later he was licensed to preach by the Carlisle Presbytery.  He was ordained in 1801.

His career as a minister bloomed when in that same year he became the pastor of the united congregations of Mifflin and Lost Creek in Huntingdon County, Pennsylvania.  In the spring of 1805 Brown was able to return to teaching when, as the first pastor of the Washington Presbyterian Church, he became the principal of the academy the church sponsored there.  A year later, thanks largely to his influence with the state legislature, the academy was chartered as Washington College.  Brown was elected the new institution's first president on December 13, 1806.  Ten very busy years as both minister and president came to an end in 1816 when Brown resigned from the college to concentrate on his pastoral duties with the local church.

Brown is said to have turned down the presidency of Centre College in Danville, Kentucky.  He did leave his congregation, however, when in 1822 he was named as the president of Jefferson College in Canonsburg, Pennsylvania, just ten miles from the college he had helped to found fifteen years before.  He served in this position for twenty-three years, during which his energy helped advance the institution in its rivalry with its neighbor, Washington College.  His efforts earned him honorary doctor of divinity degrees from Princeton, Hamilton, and Jefferson.  In 1845, he retired on the grounds of declining health, although he continued to preach as a visitor.  Matthew Brown died in Pittsburgh, Pennsylvania at the home of his son-in-law, Rev. Dr. Riddle on July 29, 1853, and was buried at Washington, Pennsylvania.  Twelve years later, the two neighboring institutions he had done so much to found merged in March 1865 to form Washington and Jefferson College.