Kimmel founded Jones Apparel Group in 1970 while working at W. R. Grace and Company. Five years later, he purchased the company with a partner. Notable lines produced by Kimmel include: Jones New York, Evan-Picone, 9 West; licensing deals with Ralph Lauren. He stepped down as chief executive officer of Jones in 2002 and sold most of his shares in the publicly traded company, but remained chairman of the board of Directors until the sale of the company to Sycamore Partners in 2014. He owns art, real estate, a movie production outfit Sidney Kimmel Entertainment, and a small stake in the professional NBA basketball team Miami Heat.

In 1993, Kimmel founded the Sidney Kimmel Foundation. The foundation's Cancer Research division pledged to contribute $120 million to institutions serving Health care, education, arts and culture. Later, in 2001, the Sidney Kimmel Foundation for Cancer Research donated $150 million to Johns Hopkins University. The donation became the largest single gift ever received by the University, and was directed toward the development of a residence for cancer patients undergoing extended treatment. The gift inspired the university to name the residence the Sidney Kimmel Comprehensive Cancer Center. In total Kimmel has his name attached to four separate cancer-research centers in Philadelphia, San Diego and Baltimore. The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital as well as the Kimmel Cancer Center at Thomas Jefferson University Hospital carry his name. The Jefferson Medical College was renamed the Sidney Kimmel Medical College of Thomas Jefferson University in June 2014, following a $110 million grant from the Sidney Kimmel Foundation, the fifth-largest ever gift to a medical school. As of April 2003, Kimmel and the Sidney Kimmel Foundation had donated an estimated $400 million.

Kimmel has also contributed over $35 million to the center for the performing arts in Philadelphia, which is now named The Kimmel Center for the Performing Arts and is home to the world-renowned Philadelphia Orchestra. Other contributions from Kimmel include a $5 million donation to The National Constitution Center in Philadelphia; a $20 million donation to Raymond and Ruth Perelman Jewish Day School in Philadelphia and $25 million for the establishment of a new prostate and urological cancer center at Memorial Sloan-Kettering in New York. In 2003 Kimmel pledged $25 million to The National Museum of American Jewish History in Philadelphia. The construction was said to have cost in total $100 million, and opened in 2006 on the museum's existing site facing Independence Mall. Kimmel donated $25 million to Stand Up To Cancer.

Founded in 2004, Sidney Kimmel Entertainment (SKE) is a Los Angeles-based production, Finance and distribution company headed by Kimmel. Films produced include SKE and Screen Gems' 2010 remake Death at a Funeral, The Kite Runner (2007), United 93, Breach, Lars and the Real Girl, Adventureland, Death at a Funeral, Synecdoche, New York, Gone (2012), The Place Beyond the Pines (2012) and The Age of Adaline.