Zellweger and Clooney are due to attend the film's UK premiere
George Clooney's Leatherheads opened at number three at the North American box office chart, despite initial figures placing it at number two.
The 1920s sports comedy had been expected to knock 21 off the top slot, but only made $12.7m (£6.4m) - $2.6m (£1.3m) less than the gambling film.
Jodie Foster's fantasy movie Nim's Island made its debut in second place.
Animated film Dr Seuss' Horton Hears A Who! dropped two places to four and at number five was horror film The Ruins.
Clooney and his co-star Renee Zellweger are due to attend the London premiere of their new film on Tuesday.
US & CANADA BOX OFFICE
1. 21 - $15.3m
2. Nim's Island - $13.2m
3. Leatherheads - $12.7m
4. Dr Seuss' Horton Hears A Who! - $9.1m
5. The Ruins - $8m
Figures for Friday-Sunday
Source: Media by Numbers
Zellweger, 38, plays a news reporter in the movie, which was directed by Clooney.
It is the 46-year-old's third directorial outing after debuting behind the camera with Confessions of a Dangerous Mind in 2002.
Spoof film Superhero Movie reached sixth place after making $5.4m (£2.7m), followed family drama Tyler Perry's Meet the Browns.
Owen Wilson's latest comedy Drillbit Taylor, about three children who hire a bodyguard to protect them from a playground bully, was at number eight.
Shutter, a remake of a Thai horror movie about a hit-and-run ghost haunting her killer, with was in ninth place, and rounding off the top 10 was Stone Age epic 10,000 BC.