In 1992, Applegate joined other celebrities in a benefit show for a Hollywood children's charity, acting as a special guest assistant to a local magician and taking part in a number of illusions, including being sawn in half. In 2003, she was the spokesperson for the Lee National Denim Day, which raises millions of dollars for breast cancer education and research.
Following her diagnosis with breast cancer, Applegate appeared on a television special entitled Stand Up to Cancer designed to raise funds for breast cancer research. The one-hour special was broadcast on CBS, NBC, and ABC television networks on September 5, 2008. In 2009, she announced her plans to return as the ambassador for Lee National Denim Day. Also in 2009, she founded Right Action for Women, a charitable foundation dedicated to breast cancer screening for women, and focused on the type of MRI scan which saved her life.
