Get Smart, in which Carell reprises the role of the bumbling spy Maxwell Smart made famous by Don Adams in the spoof TV series of the late 60s and 70s, opened at number one on $39.2m.
Anne Hathaway, Dwayne Johnson, Alan Arkin and Terence Stamp also star and Peter Segal directed.
By comparison The Love Guru, Myers' first original creation since Austin Powers, flopped in fourth place on $14m, marking a disappointment for Paramount and Spyglass who co-financed it.
Myers plays Guru Pitka, an American raised outside his country who returns as a self-help advisor. Jessica Alba and Justin Timberlake also star and Marco Schnabel directed.
Overall box office was up 10% on the same weekend last year, when Evan Almighty starring Carell opened at number one. The top 12 pictures combined for $136.9m and reports on Sunday suggested last year's $4bn record summer may be bettered in the coming months.
Paramount's Kung Fu Panda held in second place in its third weekend on $21.7m for $155.6m while Marvel Studios' The Incredible Hulk, released in North America through Universal, slipped to third and fell approximately 61% in its second weekend on $21.6m for $96.5m.
Flash back to 2003 and Hulk dropped $69.7% in its second weekend in approximately 160 more theatres and grossed $18.8m for $100.6m. It finished on $132.2m, which The Incredible Hulk should pass.
Marvel Studios' Iron Man, released through Paramount, crossed $300m in its eighth weekend and ranks ninth on $304.8m.
Fox's The Happening slipped two to fifth and stands at $50.3m while Indiana Jones 4 ranks sixth on $290.8m.
Kitt Kittredge: An American Girl opened well in limited release through the moribund Picturehouse in limited release. The film stars Abigail Breslin and grossed $223,000 from five venues.
Next weekend's wide releases are: Disney/Pixar's Wall-E and Universal's graphic novel adaptation Wanted starring James McAvoy and Angelina Jolie.
Estimated Top 10 North America Jun 20-22, 2008
Film (Dist)/Int'l dist/Est wkd gross/Est total to date
1 (-) Get Smart (Warner Bros) WBPI $39.2m -
2 (2) Kung Fu Panda (Paramount) PPI $21.7m $155.6m
3 (1) The Incredible Hulk (Universal) UPI $21.6m $96.5m
4 (-) The Love Guru (Paramount) PPI $14m -
5 (3) The Happening (Fox) Fox Int'l $10m $50.3m
6 (5) Indiana Jones And The Kingdom Of The Crystal Skull (Paramount)
PPI $8.4m $290.8m
7 (4) You Don't Mess With The Zohan (Sony) SPRI $7.2m $84.1m
8 (6) Sex And The City (New Line/Warner Bros) NLI $6.5m $132.4m
9 (7) Iron Man (Paramount) PPI/Various $4m $304.8m
10 (8) The Strangers (Rogue/Universal) UPI $1.9m $49.6m