The R-rated Marvel blockbuster is now the eighth biggest domestic opening movie of all time after making $220 million in North America alone.
Reacting on his Instagram Story, Deadpool actor Ryan, 47, wrote: "This is kind of hard to process. But thank you to everyone who went to see the film this weekend... wow."
Hugh Jackman (Wolverine), 55, wrote: "Deadpool and Wolverine is the #1 movie in the world. Thank you ALL."
Ryan recently divulged that he changed the title of 'Deadpool and Wolverine' because Internet leakers "hated" the Shawn Levy flick's original name.
He chose to change the name in February after online sleuths went ballistic after learning the film was called 'Deadpool and Friend'.
During an appearance on 'Jimmy Kimmel Live!' - on which the movie's stars filled in as guest co-hosts - He explained: "I've never told this story anywhere, but the movie was originally called 'Deadpool and Friend'. I am actually not joking.
"On the eve of the Super Bowl, the Super Bowl is where we first launched the trailer for Deadpool — not Friend, but Wolverine — it leaked because of the internet.
"The title leaked. We looked at it and listened, and they hated that title. We were not feeling so good about that anymore."