The main cast and their main parts are as follows: Seth MacFarlane, who is the creator of Family Guy and also voices Peter Griffin, Stewie Griffin, Brian Griffin, Glenn Quagmire, and Tom Tucker, Alex Borstein as Lois Griffin, Loretta Brown and Trisha Takanawa, Seth Green as Chris Griffin and Mila Kunis as Meg Griffin. The main cast do voices for several recurring characters other than those listed, as well as impersonate celebrities and pop-culture icons.

Recurring cast members include: Patrick Warburton as Joe Swanson, Mike Henry as Cleveland Brown, Adam West as the mayor Adam West, Jennifer Tilly as Bonnie Swanson, John G. Brennan as Mort Goldman, Nicole Sullivan as Muriel Goldman Catlos Alazraqui as Jonathan Weed (until the character was killed off in season three); Butch Heartman as Dr. Hartman, the family doctor, and other various characters, and Lori Alan as Diane Simmons.