He was born July 1, 1730 at West Brewster, Massachusetts the son of Joshua and Mary Sears. He was a descendant of Richard Sears, who emigrated to the colonies from Colchester, England, in 1630. While he was a child the family moved to Norwalk, Connecticut.
At the age of sixteen he was apprenticed to the skipper of a coastal vessel. By 1752, he was in command of a sloop trading between New York and Canada. Isaac established his reputation as a privateer during the French and Indian War, commanding a vessel from 1758 until 1761, when he lost his ship. He moved to New York City and had become successful enough to become a merchant investing in ships engaging in trade with the West Indies.
In 1766, Sears, John Lamb and three others formed a committee of correspondence to communication with other Sons of Liberty groups in other provinces. After the Stamp Act was repealed the Sons of Liberty erected a Liberty pole to celebrate. When the British cut down the pole for the first time, Sears was injured in a confrontation with the British. In 1768, he and numerous New York merchants sent a petition to Parliament outlining their grievances on the state of trade. In 1769, when the New York assembly passed an appropriation for funding of the Quartering act, he had posted an inflammatory broadside entitled "To the betrayed inhabitants of the city and colony of New York".
In January 1770, confrontation led by Sears with the British over the posting of broadsides and the liberty poles resulted in the Battle of Golden Hill. The fifth liberty pole was raised in 1770 on a plot of land owned by Sears. When the Tea Act was passed in 1773, he organized the city's captains into refusing to freight the East Indian tea. It was the first organized opposition to the tax. Broadsides, signed "The Mohawks", were posted warning against anyone trying to land tea. New York's opposition was partly responsible for Boston's decision to stop the landing of tea. Adams wrote, "we must venture, and unless we do, we shall be discarded by the sons of liberty in the other colonies". They were successful in preventing the landing of tea. In April 1774, they boarded the Nancy and destroyed its tea.
When in May, 1774 news of the Boston Port Act arrived, Sears and McDougall wrote a letter of support to Boston, without consulting anyone else, in addition to a British boycott, they proposed a ban on exports to the West Indies and called for a Continental Congress. Reaction in New York to the Boston Port Act was cautious and equivocal, there was a split with the DeLanceys on whether to proceed with nonimportantion.
In 1774, he was a leading member of New York City's Committee of Sixty. In a letter to the Boston Committee of Correspondence he proposed a meeting of delegates from the principal towns. This proposal was initially disavowed by the Committee of Sixty, but later was ratified in a proposal for the meeting of the First Continental Congress.
On November 20 1775, Sears led a group of 80 citizens in apprehending Parson Seabury, Judge Fowler, and Lord Underhill. At some point the mob forced Fowler to write (or else they forged his name) an apology and a promise not to interfere with the Second Continental Congress. While some of the mob escorted the three prisoners to Connecticut, Sears led the remaining 75 in a march to James Rivington's Royal Gazette, where they destroyed the printing press (which was melted and made into bullets (presumably for the war effort) in November 1775. According to the Diary of the American Revolution, Volume I:
The group then disarmed many of the loyalists along their route before disbanding.