Trimble was born in Berkeley County, Virginia, to William Trimble and Mary McMillan. His family moved to Kentucky when he was three years old. They settled in the area outside Boonesboro (now Clark County).
Trimble's opportunities for early education were sparse, but he studied what material was available and taught school for a few years. He studied law at a new law school in Lebanon, Ohio. He also read law under George Nicholas until Nicholas' death in 1799, then continued his studies under future Louisiana Senator James Brown. He was licensed to practice law by the Kentucky Court of Appeals in 1803 and commenced practice in Paris, Kentucky.
Trimble married Nancy Timberlake and the two had at least six children.
In 1803, Trimble was elected to represent Bourbon County in the Kentucky House of Representatives. During his single term in the legislature, he found that he disliked the life of a politician, and thereafter refused election to any public office, including two nominations to the U.S. Senate.
In 1808, Trimble was commissioned as an associate justice on the Kentucky Court of Appeals, where he was a colleague of future U.S. Attorney General Felix Grundy. He was offered elevation to chief justice of the court in 1810, but declined because his financial situation dictated that he return to his legal practice.
President James Madison appointed Trimble U.S. Attorney for the District of Kentucky in 1813. On January 28, 1817, Madison nominated Trimble to a seat on the United States District Court for the District of Kentucky vacated by the death of Harry Innes. Trimble was quickly confirmed by the United States Senate on January 31, 1817, and received his commission the same day.
On April 11, 1826, President John Quincy Adams nominated Trimble to a seat on the Supreme Court of the United States vacated by the death of Justice Thomas Todd. Trimble was Adams' only appointment to the Supreme Court and the first U.S. District Judge to be appointed 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 again confirmed by the United States Senate on May 9, 1826, and received his commission the same day.
As a member of the court, Trimble generally agreed with the opinions of Chief Justice John Marshall. In a notable departure, he wrote the majority opinion in the case of Ogden v. Saunders; Marshall wrote the dissenting opinion in the case. Trimble served on the Court until his sudden death from a "malignant bilious fever" on August 25, 1828. He died in Paris, Kentucky and was buried in the Paris Cemetery. Trimble County, Kentucky is named in his honor.