Each team would be sending its winningest pitcher to the mound in the opener as two tall right-handers, Vern Law and Art Ditmar would oppose each other. According to Bucs manager Murtaugh, Law had fully recovered from the mild ankle sprain he suffered a few days before. Murtaugh also had shortstop Groat back in his familiar number-two slot in the order. While he was not certain Groat would be able to perform at 100 percent so soon, he said, "I've never seen anyone with greater determination. Were it anyone except Dick, I might have my doubts."

After the opening festivities were complete, Yankee shortstop Tony Kubek led off by singling sharply off the third-base bag. He was quickly erased when Hector Lopez bounced into a double play, bringing Maris to the plate for his World Series debut. He promptly delivered a Law offering deep into the right field upper deck for a quick 1-0 New York lead. It didn't stand long, however, as Pittsburgh came right back in the bottom of the first, sending Ditmar to an early shower. Bill Virdon led off with a walk, and when he attempted a delayed steal, caught Kubek off guard. Berra threw down to second, but with no one to cover the bag, the throw sailed into center, and Virdon scampered to third. Kubek convinced the official scorer later that due to his negligence in failing to cover, the error belonged to him rather than Yogi. Groat then doubled into the right-field corner, bringing home Virdon with the tying run. Skinner singled, scoring Groat, and after Dick Stuart lined out, Clemente singled to score Skinner. Before Ditmar could even record the second out, Stengel went to the bullpen to bring in Jim Coates, who retired the two batters he faced. With one inning in the books, Pittsburgh held a 3-1 lead.

The Yankees thought they had something going in the top of the second when Berra led off with a single and Bill Skowron followed with another. In a rather unusual move, Stengel sent veteran left-handed hitter Dale Long up to pinch-hit for third baseman Clete Boyer with no outs in the second, but the strategy failed as Long flied to right with no advancement of the runners. Bobby Richardson then lined to Skinner in left, who then doubled Berra off second to quell the rally.

The bespectacled Virdon made what was likely the play of the game off of Berra in the Yankee fourth. Maris reached safely again in his second at-bat, singling to right center, and Mantle then walked, which brought up Berra with nobody out. Yogi launched a 410-foot fly to deep right center field which both Virdon and Clemente pursued. Though they collided slightly, Virdon managed to come up with a spectacular one-handed catch, getting spiked by Clemente in the process. Murtaugh said afterwards, "Yogi whaled the daylights out of that ball, but Bill got us out of a big inning." Virdon added, "It was not my greatest catch, but it was certainly the most enjoyable." The Yankees did score one that inning on a Skowron single, and Pittsburgh held a slim 3-2 lead going into the bottom of the fourth.

The Pirates then came to bat, and with one down, Don Hoak was issued a walk from Coates. Mazeroski then came up, having been struck out by Coates in his first at-bat in the second inning. Here in the fourth Maz was challenged with the first two pitches over the heart of the plate, and found himself in the hole 0-2. Maz said later that he thought Coates would waste one in this situation but came in with a letter-high fastball that he pulled over the left-field wall for what would later become the second-most famous home run of his entire career. It was also the first homer he had hit at Forbes Field since July 16. Pittsburgh now held a 5-2 advantage, and though the scoring wasn't finished, they would not relinquish the lead.

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