Trimble was born in Berkeley County, Virginia, to William Trimble and Mary McMillan. His family moved to Kentucky while he was still an infant settling in the area outside Boonesboro (now Clark County.)

He was licensed to practice law in 1803. He served in the Kentucky House of Representatives from Paris, Kentucky in Bourbon County. He also served briefly on the Kentucky Court of Appeals. He was the federal prosecutor and later appointed United States District Judge for Kentucky by President Madison.

Trimble married Nancy Timberlake and the two had at least six children.

He was appointed to the U.S. Supreme Court in 1826 by President John Quincy Adams after the death of Justice Thomas Todd. He was John Quincy Adams' only appointment to the Supreme Court. Adams is said to have appointed Trimble because of the "Kentucky" vacancy created by the death of Thomas Todd and on the advice of Henry Clay, who was Secretary of State.

Trimble was the first U.S. District Judge to be appointed to the Supreme Court. He served on the Court until his sudden death in Paris, Kentucky, in 1828. He is buried in the Paris Cemetery. Trimble County, Kentucky is named in his honor.