As a young man, McKendree served in the Virginia militia during the American Revolutionary War.

He soon volunteered to take part in public religious meetings, and his addresses produced a powerful effect.

In 1788, while living in Brunswick County, Virginia, William was received on trial into the ministry of the Methodist Episcopal Church.

McKendree continued as an itinerant preacher until November 1792, when, having been influenced by James O'Kelly to join in certain measures of pretended reform, he was greatly disappointed by their failure at the General Conference.

McKendree soon obtained leave to travel with Bishop Asbury, that he might ascertain for himself whether his impressions had been well founded.

In 1801, the conference sent McKendree to oversee the church's efforts in Southeastern Ohio, Kentucky, Tennessee, and western Virginia and part of Illinois.

He served as a circuit preacher in addition to his organizational efforts, becoming a respected figure in the region.

William McKendree became widely know and most highly esteemed because of his popular talents in the pulpit and his faithful attention to every part of his work.

He died 5 March 1835 at the home of his brother, Dr. James McKendree, in Sumner County near Nashville.

His mind was clear and logical, his knowledge varied and extensive, his imagination lively but well regulated, and his eloquence was unusually powerful.

He was careful in the administration of discipline, and intruduced system into all the operations of the church.Bishop McKendree's influence was patent everywhere, but especially was he regarded in the West.