Mathew Carey retired in 1825, leaving his prosperous business in the hands of his son Henry Charles Carey and son-in-law Isaac. The publishing house became one of the most successful in America, publishing among others The Encyclopedia Americana, a dictionary of German lexicon, as well as American editions of the works of Walter Scott and James Fenimore Cooper. The firm promoted William A. Blanchard to partner in 1833, and when Mathew Carey died in 1838 and Henry Carey retired in 1846, the publishing house’s name changed to Lea & Blanchard, and it became Lea Brothers when his sons entered into the business and Isaac himself retired to pursue his scientific interests. In the 1840s, the Careys were staunch nationalists and economic protectionists.

He was a member (and for a time vice-president) of the American Philosophical Society and also served as President of the American Academy of Natural Sciences(1858–1863), both based in Philadelphia. Isaac Lea served as President of the American Association for the Advancement of Science in 1860.

He died on December 8, 1886, and is buried in Philadelphia’s Laurel Hill Cemetery. In 1829 Edgar Allan Poe wrote a poem dedicated to Lea called “To Isaac Lea”.