Meigs was born in Middletown, Connecticut, in 1740. He served in the local militia, advancing to the rank of captain in 1774. On April 19, 1775, after the Battle of Lexington, he led a company of light infantry to Boston. There he was assigned the rank of major in the Continental Army. Later that year, serving as division commander under Colonel Benedict Arnold, he accompanied Arnold on his expedition through Maine to Canada. He was captured by the British in the assault on Quebec City and imprisoned, but was released in May 1776, after which he returned to Connecticut and subsequently returned to military service. In 1777 he was promoted to colonel.
One of his most important achievements during the Revolutionary War was leading the Meigs Raid against the British forces in Sag Harbor, New York, in May 1777. With 220 men in a fleet of 13 whaleboats, he crossed Long Island Sound from Connecticut to Long Island to attack the British fleet at night. The raid succeeded in burning 12 ships and taking 90 prisoners, without losing a single man. The U.S. Congress awarded him a presentation sword for his heroism. He later commanded a regiment under General Anthony Wayne at the Battle of Stony Point.
After the war Meigs was appointed surveyor of the Ohio Company of Associates, which is credited as bringing the first non-American Indian settlers to Ohio. In April 1788 he founded the town of Marietta and drew up the code of regulation used until the formal creation of the Northwest Territory the following year. In the territory, Meigs served as a judge, justice of the peace, and clerk of courts, and served in the General Assembly from 1799 to 1801.
In 1801 Meigs went to Tennessee to fill the combined position of agent to the Cherokee Nation and military agent for the United States War Department. Initially his office and Cherokee Agency were at Fort Southwest Point in what is now Kingston, Tennessee, but in 1807 he relocated these operations to a new post named Hiwassee Garrison near the mouth of the Hiwassee River. His role as military agent ended in 1813 when the Federal soldiers stationed at Hiwassee Garrison were withdrawn, but he remained as Cherokee agent on the Hiwassee River until his death on January 28, 1823. During his years as Cherokee agent he promoted the well-being of the Cherokees, defended their rights in treaty negotiations, and encouraged Cherokee efforts to establish a republican form of government.
He is buried in the Garrison Cemetery in Rhea County, Tennessee, near the site of the former Hiwassee Garrison.
His son Return J. Meigs, Jr. became an Ohio governor and senator. His great-grandson Brig. Gen. Montgomery C. Meigs and great-great grandson of Maj. John Rodgers Meigs had distinguished military careers. Montgomery Meigs, also a general, is also a descendant.