Kevin Feige served as an associate producer on X-Men (2000), and was present at Hugh Jackman's original audition for Wolverine. Feige said, "For [Jackman], and for me, and I think for all of the fans of Marvel, it's unbelievable what has happened in 23 years... to have Hugh come back is incredible. For me, personally, that is where I started. It was his first on-set audition, and he flew up to Toronto to do a read with Anna Paquin. I remember sitting behind the camera, well behind the camera, at his audition... It's very full-circle having him come back in this new Deadpool film."
Hugh Jackman said he really was done playing the character of Wolverine after Logan (2017). When asked why he chose to return for this film, he simply said, "I just wanted to do it, and I felt it in my gut."
In X-Men (2000), Wolverine says of the team's suits, "You actually go outside in these things?" to which Cyclops responds, "What would you prefer? Yellow spandex?" The live-action Wolverine would not appear in his signature yellow costume until this movie, 24 years after the release of the first X-Men movie. Director Shawn Levy said, "Like the rest of the world, I've waited two decades to see Wolverine in a whole movie with Deadpool, and I don't know if this is our last shot at Wolverine on screen, so I was going to make goddamned sure we get the old yellow and blue just once, and that we get it right." Hugh Jackman said, "How did we never do this? It looked so right, it felt so right. I was like, 'That's him.'"
Jennifer Garner is confirmed to reprise her role as Elektra Natchios from Daredevil (2003) and its spin-off Elektra (2005).
Jay Fear, a terminally ill 45-year-old Wrexham FC fan (a football club which Ryan Reynolds co-owns in the UK) got to meet Reynolds at the Wrexham v Boreham Wood league match in April 2023, thanks to a charity called Bucket List Wishes who were contacted by nurses looking after Mr. Fear. At the meeting, Reynolds gave him one of the gloves from his Deadpool costume and arranged for him to visit the Deadpool and Wolverine film set at Pinewood Studios. After Mr. Fear died the following month, Reynolds posted a heartfelt tribute to him via social media.