Zito's sublime effort, in which he didn't allow a hit until Rondell White's two-out double in the fifth inning, was backed by two home runs from Frank Thomas, and Oakland's tense 3-2 victory stopped cold Santana's remarkable 16-game winning streak at home.
"To beat Rocket at Yankee Stadium was definitely No. 1 before today," Zito said. "But beating Johan in this place? I might have to rethink that one. Flip a coin. They're both pretty incredible feelings."
A's general manager Billy Beane used the word "incredible" in describing Zito's performance. He also suggested that he expected -- well, sort of -- his club to end the remarkable streak of Santana, whose last loss here came on Aug. 1, 2005, also against the A's.
"You know what? I actually felt pretty good about it," Beane said. "One, Barry is at his best in this kind of situation. He's come up huge under pressure before. Two, you know me; I'm a mathematical guy. Sixteen-and-oh since 2005? Something's gotta give."
In the much-hyped matchup of former Cy Young-winning lefties, Zito (2002) and Santana (2004) didn't give much.
"Johan threw the ball great," A's center fielder Mark Kotsay said of Santana, who gave up two runs on five hits and a walk. "But Barry's been here before ... he's won in this building in the playoffs [in 2002], and I think he used all of those elements to his advantage today. He was extremely motivated."
Closer Huston Street, who gave up a run in the ninth after right fielder Milton Bradley lost Michael Cuddyer's leadoff fly ball in the roof but picked up the save in his postseason debut, seemed nothing short of in awe of what Zito had done.
"That's why he's Barry Zito, Cy Young winner," Street said. "That's why we want to keep him here in Oakland, and why we probably can't afford him. Beating Santana in his house? Wow."
"Big-time players step up in big-time games," added A's first baseman Nick Swisher. "And Barry's one of our big-time guys."
As is Thomas. Santana tore through the top of the first inning, striking out two, but Thomas led off the second with a towering home run just inside the left-field foul pole.
"I can't even tell you how huge that was," Zito said. "It frees you up in a way that's really hard to describe. Frank has been carrying us for a long time, so nothing he does surprises me, but you still kind of drop your jaw and say, 'Bro, are you kidding me?' Amazing lift for me as a pitcher, and for us as a team.
"First blood means a lot, especially when you're playing on the road."
Eric Chavez struck out after Thomas' homer, but Jay Payton followed with a single up the middle, and Marco Scutaro drilled a two-out double down the line in left off his fellow Venezuelan, bringing Payton all the way around for a 2-0 lead.
"Marco's hit was just as big as Frank's first homer," Street said. "That took their advantage -- the crowd -- out if the equation."
The A's didn't get another hit until Kotsay singled to center in the sixth, and he was quickly erased when Bradley hit into an inning-ending double play. After throwing 50 pitches through the first three frames, it took Santana all of 18 pitches to navigate the next three.
"He was dominant," Swisher said. "Just like Santana always is. His changeup is absolutely evil."
Zito, meanwhile, was similarly efficient. He walked Luis Castillo to open the top of the first, but Castillo was caught stealing by Jason Kendall, and though he again walked Castillo in the fourth, Zito cruised through the first six innings.
"Kendall throwing out Castillo is the underrated play of the whole game," Zito said. "If that inning snowballs, then it's me pitching from behind, it's their crowd going nuts, and we're pushing a huge boulder uphill the rest of the day."
A single by Castillo and a two-out walk to Joe Mauer finally brought the sellout crowd to life in the sixth, but Zito hushed the Homerdome by getting Cuddyer to bounce into a forceout with his 73rd pitch of the game.
"He was speeding us up, slowing us down, in and out," Cuddyer said. "When he's going good like today, that's what he does; he messes with your timing and he messes with your eye level. He pitches off that breaking ball, he gets your eye level up, and he messes with what you're trying to do."
The A's had a chance to reward Zito with an insurance run in the top of the seventh when they loaded the bases on a walk to Thomas, an error by shortstop Jason Bartlett and a one-out walk to Swisher, but Scutaro's line drive to center fielder Torii Hunter was too shallow to tempt Thomas into testing Hunter's strong arm, and Mark Ellis flied out to left.
That lost opportunity was magnified when White cut the lead in half with a two-out solo bolt into the left-field bleachers in the bottom of the inning, and it looked like it might loom even larger in the eighth when Bartlett led off with a double.
But after almost getting picked off second by Kendall, who had him dead in the water if his throw hadn't sailed wide, Bartlett had to hold his ground when Castillo grounded out to third base. He moved up to third when Nick Punto grounded out to second, but he was left there when Zito got Mauer, the AL batting champion, to line out softly to left field.
"He throws that big slow curve, then he gives you that 86-87 mile-an-hour fastball [that] looks like it's 91," Hunter said of Zito. "He put it on us today."
Jesse Crain took over for Santana to start the ninth, and Thomas greeted him by slamming a 1-1 pitch deep into the seats beyond the wall in left.
"Like I said, big-timers show up this time of year," Swisher said. "And it doesn't really get any more big-time than Frank Thomas."
Nor does it get much bigger than beating Clemens with your team's season on the line. Scutaro wasn't with the A's when Zito pulled that off, so this one is the No. 1 Zito highlight in his book, hands down.
"He was like an artist," Scutaro said. "That guy was painting today, man. Wherever Jason put the target, Barry put it right there. Normally he throws a lot of pitches, but what did he throw today,  in eight innings? That's painting.