Santana (4-7) came into the game having allowed 23 earned runs in his previous four starts, and there was talk he might lose his spot in the rotation when Jered Weaver returns from the disabled list.
In fact, former Angel and current D-back Joe Saunders told his longtime friend Friday to keep his head up with all the struggles.
Little did Saunders know that Santana turning around his fortunes would mean that Saunders would walk away from Saturday's start with a loss.
"I think I had some good words of advice, obviously," Saunders said.
Saunders was pretty good himself on Saturday.
After allowing a home run in the first inning, Saunders kept the Angels off the board the rest of the way before departing after the sixth.
"Joe pitched a great game for us," Gibson said. "Battled his tail off for us. He gave us a chance to win the game. We were just unable to do so."
That's because Santana was simply better.
One by one, the first 20 D-backs hitters failed to reach base against Santana. There were no great defensive plays to keep the perfect game in place, and there was just one hard-hit ball, a flyout to the left-field wall by Henry Blanco to end the third.
"I hit it pretty good," Blanco said. "It's tough for me to say I got it, but I hit it pretty good. I guess it was too high, I don't know. I was battling the whole at-bat and got a good pitch to hit."
Even when Santana fell behind in the count, which he did quite a bit early on, the D-backs were unable to capitalize.
As it got later in the game, the announced crowd of 42,483 was buzzing in anticipation of possibly witnessing history.
"When you get to the sixth and nothing's happening, of course you've got to think about it," Santana said. "But at the same time, you have to refocus and keep pitching."
Finally, in the seventh, Upton jumped on a first-pitch fastball and singled sharply up the middle for Arizona's first hit.
"I just saw a fastball first pitch and swung the bat," Upton said. "I was able to barrel that one up, and it got through. To be honest with you, I thought we swung the bat well. He was mixing it up on us, and we couldn't really square him up."
Other than Upton, the only other runner to reach was pinch-hitter Miguel Montero, who drew a one-out walk in the ninth. Santana fanned five and needed just 102 pitches to complete the masterpiece.
It was impossible to know it at the time, but the game was lost for Saunders (4-5) and the D-backs in the first inning when Mark Trumbo hit a two-out, two-run homer.
With one out in the inning, Saunders allowed a single to Torii Hunter before getting Albert Pujols to strike out looking.
Trumbo then worked the count to 3-2, and Saunders decided to throw him a curveball.
"Just tried to throw a breaking pitch and maybe surprise him on a 3-2 count, and he stayed back on it," Saunders said.
The veteran pitched his way out of jams the rest of his outing.
"It was a battle tonight," Saunders said. "I felt like I didn't have my best stuff, but just tried to battle and keep my team in it as best I could."
Saunders battled some early nerves in pitching in Angel Stadium for the first time since he was dealt to the D-backs in July 2010.
"It was different, for sure," Saunders said. "There was definitely some butterflies. You just keep telling yourself it's another ballgame. It was definitely strange. I was telling myself, 'Just don't go to the third-base dugout.'"