He was known as a very energetic person with high ability. In 1788, he was a member of the Connecticut convention that ratified the United States Constitution. He was elected to the Connecticut General Assembly several times and in 1796 was commissioned brigadier general of militia. He was a shareholder in the Connecticut Land Company, which had purchased for $1,200,000 from the state government of Connecticut the land in northeastern Ohio reserved to Connecticut by Congress, known at its first settlement as New Connecticut, and in later times as the Western Reserve. He was approached by the directors of the company in May 1796 and asked to lead the survey of the tract and the location of purchases. He was also responsible for the negotiations with the Native Americans living on the land. In June 1796, he set out from Schenectady, New York. His party included fifty people including six surveyors, a physician, a chaplain, a boatman, thirty-seven employees, a few emigrants and two women who accompanied their husbands. Some journeyed by land with the horses and cattle, while the main body went in boats up the Mohawk, down the Oswego, along the shore of Lake Ontario, and up Niagara River, carrying their boats over the long portage of seven miles at the falls.

At Buffalo a delegation of Mohawk nation and Seneca tribe Indians opposed their entrance into the Western Reserve, claiming it as their territory, but waived their rights on the receipt of goods valued at $1,200. The expedition then coasted along the shore of Lake Erie, and landed, on July 4, 1796, at the mouth of Conneaut Creek, which they named Port Independence. The Indians were propitiated with gifts of beads and whiskey, and allowed the surveys to proceed. General Cleaveland, with a surveying party, coasted along the shore and on July 22, 1796, landed at the mouth of the Cuyahoga River. He ascended the bank, and, beholding a beautiful plain covered with a luxuriant forest-growth, divined that the spot where he stood, with the river on the west and Lake Erie on the north, was a favorable site for a city.

He accordingly had it surveyed into town lots, and the employees named the place Cleaveland, in honor of their chief. There were but four settlers the first year, and, on account of the insalubrity of the locality, the growth was at first slow, reaching 150 inhabitants only in 1820. Moses Cleaveland went home to Connecticut after the 1796 expedition and never returned to Ohio or the city that bears his name. He died in Canterbury, Connecticut. Today, a statue of him stands on Public Square in Cleveland.

The place called "Cleaveland" eventually became known as "Cleveland". In 1830, when the first newspaper, the "Cleveland Advertiser," was established, the editor discovered that the head-line was too long for the form, and accordingly left out the letter "a" in the first syllable of "Cleaveland," which spelling was at once adopted by the public. Great Lakes Brewing Company has created a white ale in his honor dubbed "Holy Moses White Ale".