Martin was an early advocate of American independence from Great Britain. In the fall of 1774 he served on the patriot committee of Somerset County, and in December he attended a convention of the Province of Maryland in Annapolis, which had been called to consider the recommendations of the Continental Congress. Maryland appointed Luther Martin its attorney general in early 1778. In this capacity, Martin vigorously prosecuted Loyalists, whose numbers were strong in many areas. Tensions had even led to insurrection and open warfare in some counties. While still attorney general, Martin joined the Baltimore Light Dragoons. In July 1781 his unit joined Lafayette's forces near Fredericksburg, VA., but Martin was recalled by the governor to prosecute a treason trial.

Martin married Maria Cresap on Christmas Day 1783. Of their five children, three daughters lived to adulthood. His postwar law practice grew to become one of the largest and most successful in the country. In 1785 Martin was elected to the Continental Congress, but this appointment was purely honorary. His numerous public and private duties prevented him from traveling to Philadelphia.

At the Constitutional Convention Martin opposed the idea of a strong central government. When he arrived on June 9, 1787, he expressed suspicion of the secrecy rule imposed on the proceedings. He consistently sided with the small states and voted against the Virginia Plan. On June 27 Martin spoke for more than 3 hours in opposition to the Virginia Plan's proposal for proportionate representation in both houses of the legislature. Martin served on the committee formed to seek a compromise on representation, where he supported the case for equal numbers of delegates in at least one house. Before the convention closed, he and another Maryland delegate, John Francis Mercer, walked out.

In an address to the Maryland House of Delegates in 1787 and in numerous newspaper articles, Martin attacked the proposed new form of government and continued to fight ratification of the Constitution through 1788. He lamented the ascension of the national government over the states and condemned what he saw as unequal representation in Congress. Martin opposed including slaves in determining representation and believed that the absence of a jury in the Supreme Court gravely endangered freedom. At the convention, Martin complained, the aggrandizement of particular states and individuals often had been pursued more avidly than the welfare of the country. The assumption of the term "federal" by those who favored a national government also irritated Martin. Around 1791, however, Martin turned to the Federalist party because of his animosity toward Thomas Jefferson.

The first years of the 1800s saw Martin as defense counsel in two controversial national cases. In the first Martin won an acquittal for his close friend, Supreme Court Justice Samuel Chase, in his impeachment trial in 1805. Two years later Martin was one of Aaron Burr's defense lawyers when Burr stood trial for treason in 1807.

After a record 28 consecutive years as state attorney general, Luther Martin resigned in December 1805. In 1813 Martin became chief judge of the court of oyer and terminer for the City and County of Baltimore. He was reappointed attorney general of Maryland in 1818, and in 1819 he argued Maryland's position in the landmark Supreme Court case McCulloch v. Maryland. The plaintiff, represented by Daniel Webster, William Pinckney, and William Wirt, won the decision, which determined that states could not tax federal institutions.

Martin's fortunes declined dramatically in his last years. Heavy drinking, illness, and poverty all took their toll. Paralysis, which had struck in 1819, forced him to retire as Maryland's attorney general in 1822. In 1826, at the age of 78, Luther Martin died in Aaron Burr's home in New York City and was buried in an unmarked grave in St. John's churchyard.