Smith completed 18 of 19 passes for 232 yards and three touchdowns — two to Michael Crabtree and one to Randy Moss — to help San Francisco (6-2) open a two-game lead in the division and send Arizona (4-4) to its fourth straight lost.
Smith's only incompletion was dropped by a wide-open receiver.
Smith was 14 of 15 for 146 yards and two touchdowns, both to Crabtree, as the 49ers built a 17-0 halftime lead.
Moss caught a 47-yard TD pass, dodging tacklers down the sideline on a play that seemed to turn back the clock to the receiver's prime. With the catch, he tied Terrell Owens for fourth on the NFL career touchdown list with 156.
Smith, who tied a career high with the three touchdown passes, spread out his completions to 10 receivers. Crabtree led the way with five catches for 72 yards.
Arizona's defense, supposed to be the team's strength, missed tackle after tackle in an embarrassing nationally televised performance at home. The 24 points were the most allowed by the Cardinals this season.
Led by Smith's near-perfect precision passing, the 49ers methodically dominated from the start. The San Francisco quarterback had the best completion percentage of his career, and he would have been perfect had Delanie Walker not dropped the ball when he was wide open on a crossing route in the first half.
A 10-play, 77-yard drive that consumed just over 6 minutes of the first quarter put San Francisco up 7-0. On third-and-goal from the 3, Smith threw a sidelines pass to Crabtree, who outfought Patrick Peterson for the ball and the touchdown.
A flurry missed tackles, most notably an open-field whiff by Sam Acho, helped Ted Ginn Jr. return a punt 35 yards to the Arizona 45 in the second quarter. Daryl Washington sacked Smith to help set up a third-and-23 from the Cardinals 46. But Smith found Crabtree over the middle for 22 yards, just a yard shy of the first down. David Akers' 43 yard field goal made it 10-0 with 5:58 left in the half.
Crabtree beat Peterson again for San Francisco's second touchdown. Smith threw over the middle to the receiver, who caught the ball, then fooled Peterson with an inside move into the end zone to make it 17-0 with 1:41 left in the half. The 49ers drove 68 yards in eight plays, again overcoming a sack, this one by Calais Campbell, that made it second-and-goal from the 16. Smith threw 7 yards to Mario Manningham to set up the TD toss to Crabtree.
The Cardinals were booed off the field by the home crowd at the half.
Things didn't get any better for the home team in the third quarter. On third-and-9, Smith threw 30 yards to Crabtree, who evaded a host of tacklers. Then on third-and-8, Smith tossed a short pass to Moss, who sidestepped a series of would-be defenders all the way to the end zone, putting San Francisco ahead 24-0 with 7:27 left in the third quarter.
The Cardinals averted a shutout with Jay Feely's 28-yard field goal
John Skelton, making his second start since Kevin Kolb went down with rib injuries, completed 32 of 52 passes for 290 yards, often overthrowing receivers. The Cardinals rushed for just 7 yards in nine attempts against the 49ers, who entered the game as the No. 1-ranked defense in the NFL, No. 2 against the run.
Arizona's final possession ended when Larry Fitzgerald was stopped at the 1.
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