Isaac Perlmutter was born to a Jewish family in pre-statehood Israel. He emigrated to the United States after serving in the Israeli Army during the Six-Day War of 1967. Arriving in New York City with only $250, he earned a living standing outside Jewish cemeteries in Brooklyn, leveraging his Hebrew skills to lead funeral services for tips.

With a new partner, Bernard Marden, and leveraging the skills he attained as a wholesaler, he formed a company called Odd Lot Trading, a wholesaler and retailer of closeout items. In May 1984, they sold Odd Lot to Revco Discount Drug Stores in exchange for 12% of Revco stock. He soon challenged Revco management for control of the company but, after initial positive feedback, was rejected. Perlmutter and his partner threatened a hostile takeover but eventually refrained and sold their share back to Revco for $120 million.

In 1988, he saw an opportunity as Coleco struggled under its debt due to the advent of the personal computer which impacted the sale of video games. Perlmutter bought all of Coleco's senior debt (with $85 million in face value) for $50 million, a substantial discount, becoming senior to their bondholders in the event of a bankruptcy. Although Perlmutter believed that a Coleco bankruptcy was probable, he also believed that the value of the Coleco's assets should be sufficient to cover the full $85 million in value that he had purchased. In July 1988, Coleco filed for Chapter 11 bankruptcy. The bondholders, suspicious over Perlmutter's close relationship with Coleco's management, sued Perlmutter alleging fraudulent conveyance over the barter advertising credits (which made up a very significant item on Coleco's balance sheet). After extensive negotiation, a settlement was reached whereby Coleco would be sold to Hasbro Corporation for $85 million and Perlmutter would accept $64 million for his now $90 million claim (principal plus interest) in exchange for the withdrawal of the lawsuit.

Isaac Perlmutter also was the co-owner, with Avi Arad, of Toy Biz (later Marvel Toys), having purchased its predecessor company from Charan Industries in January 1990. Toy Biz, Inc. was reorganized in the Marvel deal with Perlmutter continue owning the original Toy Biz, Inc., which is renamed Zib, Inc. Zib held its foreign sales affiliate, Toy Biz International Ltd., a Hong Kong corporation and Perlmutter's share of the new Toy Biz, Inc.

In 1993, Perlmutter and his wife established the Laura and Isaac Perlmutter Professorship and Chair in Cell Biology at the Skirball Institute of Biomolecular Medicine (part of the New York University School of Medicine). In addition, Mrs. Perlmutter has served as a trustee on the NYU Medical Center's Board of Trustees since 1993.

In 1994, Victor Kiam sold controlling interest of Remington Products to Isaac Perlmutter. Perlmutter became Vice President of Remington. Kiam and Perlmutter sold Remington to Vestar Capital Partners in 1996.

When Marvel company group went bankrupt in 1996, protracted legal battles over control of the company followed between Perlmutter, Arad, Carl Icahn, and Ron Perelman. By 1997, Perlmutter and Arad had established control over the company, pushing out Icahn and Perelman. ToyBiz and Marvel were merged into Marvel Enterprises to bring it out of bankruptcy in June 1998 with ToyBiz becoming a division of the new company.

In November 2001, Perlmutter became Vice Chairman of the Board of Directors of Marvel. He became the Chief Executive Officer of Marvel Comics on January 1, 2005. He remained CEO of Marvel Entertainment, even after the acquisition of Marvel by The Walt Disney Company on December 31, 2009. Although Perlmutter received $800 million in cash and $590 million in Disney stock after the acquisition, he did not want a seat on Disney's board of Directors.

In 2015, Laura Perlmutter donated $2 million to a Super PAC supporting the presidential candidacy of Sen. Marco Rubio.

On June 30, 2016, Laura Perlmutter donated $449,400 to a PAC supporting Donald Trump, and later was part of Trump's Inauguration committee.

In April 2017, Perlmutter was categorized by The New York Times as one of the "Clubgoers" among twenty people whom President Trump consults "outside the White House gates". He "has been informally advising ... on veterans issues [and] ... has been a presence" at Mar-a-Lago, according to the account.