SAN FRANCISCO — Since last season's surprising run to the NFC championship game, San Francisco 49ers fans could only imagine the possibilities if Alex Smith and the offense ever matched the defense's dominance.

Just Saturday night, Smith added another punchline when he badly bounced the ceremonial first pitch of the San Francisco Giants-Cincinnati Reds playoff series in the dirt. Some teased aloud whether the quarterback could even throw.

With the New York Giants returning to Candlestick Park next for the first time since ending San Francisco's season, the only one laughing now is the 49ers quarterback.

Smith had one of the most prolific passing games of his eight-year career Sunday, throwing for a season-high 303 yards and three touchdowns to help the 49ers set a franchise record with 621 total yards in a 45-3 romp over the Buffalo Bills. San Francisco became the first team in NFL history with 300 yards passing and 300 yards rushing.

"I was keeping the ball down, isn't that what good pitchers do?'' Smith joked about his pitch. "I was working the count. I had an open base.''

In the grand scheme of a 16-game season, all the records still only add up to one win against a Buffalo (2-3) team that has been embarrassed in back-to-back weeks. Even so, it's hard to overlook what San Francisco might be capable of if Smith and his receivers can play like this.

Michael Crabtree (seven catches for 113 yards) and Vernon Davis (seven catches for 106 yards) each eclipsed the century mark to pull San Francisco (4-1) into a tie with Arizona for the NFC West lead. Even Randy Moss, rarely targeted in his comeback, caught a pass for 11 yards.

Smith, the 2005 No. 1 overall pick out of Utah, threw TD passes of 43, 28 and 10 yards and surpassed 300 yards passing for only the third time in his career - and first in a victory. The last time came when he had 309 yards in a loss at Philadelphia two years ago - "a completely different world,'' he said - in former coach Mike Singletary's final season.

"Quarterback was near perfect,'' 49ers coach Jim Harbaugh said.

The Bills again found themselves on the wrong side of a 49ers record - and quite a few others, too.

Rian Lindell kicked a 31-yard field goal in the first quarter before the 49ers scored the final 42 points to hand Buffalo (2-3) its second straight embarrassing loss. San Francisco's previous best was 598 yards in a 34-31 loss to the Bills on Sept. 13, 1992, which also was Buffalo's worst.

Ryan Fitzpatrick threw for 126 yards and an interception, and the Bills rushed for only 89 yards, most with the game well out of hand once again.

"They flat-out dominated the game from end to end,'' Fitzpatrick said. "We just got beat bad by a better team today. There was no fancy stuff. They are who they are and they just played better.''

Far better.

The Bills allowed 45 second-half points and 580 total yards in a humiliating 52-28 home loss to New England last week. Beginning a two-week road trip, Buffalo's baggage also traveled to the West Coast.

Since taking a 21-7 lead against the Patriots, Buffalo has been outscored 90-10. The Patriots and 49ers combined to gain 1,201 yards. And with the 49ers shredding the New York Jets last week, they've outscored opponents 79-3 in their last two games.

The Bills became the first team to give up at least 550 yards in consecutive games in the same season since the 1950 New York Yanks.

"I have no answers and no excuses,'' beleaguered Bills coach Chan Gailey said. "I don't have the answers and I have to find the answers. That's my job.''

With the Bills unable to slow anybody down on defense, San Francisco abandoned its usually conservative game plan to deliver a scintillating show in the air.

Smith, who sprained his middle finger in the fourth quarter, completed 18 of 24 passes. He also had a perfect 158.3 passer rating in the first half, when he threw for 237 yards - a career best for a half.

The longest completion Smith had in the first four weeks was for 29 yards. In the first half alone, he completed a 53-yarder to Davis that set up a field goal by David Akers, a 43-yard touchdown to Kyle Williams and hooked up with Crabtree for 36 yards.

Williams took the back-shoulder pass from Smith, spun away from a defender and ran the final 10 yards free into the end zone. Williams fell to his knees, raised his arms and nodded to the sun-splashed crowd at Candlestick Park after giving the 49ers a 10-3 lead.

Every time the Bills blew an opportunity - and they blew plenty - the 49ers capitalized.

Backup quarterback Colin Kaepernick, who ran for 39 yards on four carries, fumbled on an end-around and Buffalo took over at its own 17. Two plays later, Patrick Willis stripped Scott Chandler, San Francisco recovered and Smith floated a 28-yard touchdown to Crabtree to put the 49ers in front 17-3 with 24 seconds to go before the half.

"Everything about today was just amazing,'' Crabtree said.

A holding penalty on Buffalo's Jairus Byrd wiped out a punt return Leodis McKelvin took for a touchdown in the first quarter. The offense failed to score any points after McKelvin returned a kickoff 59 yards. And after a 12-play, 75-yard drive that took nearly 6 minutes stalled in the second quarter, Lindell kicked a field goal for Buffalo's only score.

Smith led another touchdown drive that featured Kaepernick gaining 15 yards on a sweep and ended one play later when Gore dove over the pile for a TD that extended San Francisco's lead to 24-3.

Chris Culliver intercepted an underthrown pass by Fitzpatrick just shy of the goal line to end Buffalo's best chance to reach the end zone all afternoon.

Smith also tossed a 10-yard TD pass to Mario Manningham, Kaepernick ran 16 yards for a score and Anthony Dixon added a 3-yard run for the final touchdown.

"I'm not a big statistical guy, don't get caught up in it,'' 49ers offensive coordinator Greg Roman said. "But at the same time, just in the normal course of events to be able to throw up that kind of production, obviously we're doing something right.''