Pfeiffer and husband David E. Kelley are parents to Claudia, whom they adopted in 1993, and son John Henry, born in 1994. The actress once paused her career to focus on family, later returning to work with her children’s encouragement — as she told The Skinny Confidential Him & Her Podcast in 2023 when they asked, "Mom, are you ever gonna go back to work?"
Over the years the family appeared together at select events: the 2007 Hairspray premiere, the Stardust premiere that same year (where Claudia was her date), and they celebrated Pfeiffer’s Hollywood Walk of Fame star soon after. Other outings captured include the 2010 Oscars, the 2011 Golden Globes, the 2012 Dark Shadows premiere and intimate Instagram posts in 2021 — including a June photo "out on the town" with Claudia and a National Son and Daughter Day throwback in which she called them her "two rascals."