The Padres unexpectedly tagged Santana, a two-time Cy Young Award winner, for four runs in the first game before struggling to figure out Niese, who was making his 18th career start, in the nightcap.
Niese faced 28 batters, one over the minimum, as center fielder Chris Denorfia was the only player to reach base -- on a third-inning double -- against the 23-year-old.
"You never know how a Major League game is going to play out," Padres manager Bud Black said. "This guy in the second game really threw the ball well, no doubt. He had the hard cutter-slider working in on our hands. The nice slow breaking ball had a nice bite to it, and the fastball to the outer part of the plate against our righties. He threw the ball well."
Niese kept San Diego off balance with his curveball while pounding the strike zone, walking none and throwing 76 of his 108 pitches for strikes.
The Padres made 20 of the 27 outs on ground balls (14) or strikeouts (six) and failed to put any real pressure on New York's defense.
Though Santana is easily the more established of the two Mets pitchers -- the Padres faced him on June 2 in San Diego -- Niese's relatively unknown repertoire shut down the San Diego lineup.
"Another thing that went into it is we hadn't seen him, a lot of guys hadn't faced him," said Chase Headley, who went 0-for-3 with three groundouts. "He's a little tougher to pick up until you kind of get used to him. Unfortunately, he was rolling, and sometimes when guys get their confidence, he just kept rolling the more that we saw him. He just kept making quality pitches."
The Padres head back to San Diego for a nine-game homestand having dropped two of three to the Mets in New York, marking the first time they have lost a series since the Dodgers swept them at PETCO Park on May 14-16.
It was the third time this season that the Padres have been shut out.
The lone highlight for the Padres in the second game came when starting pitcher Jon Garland got Ruben Tejada to hit into a 5-4-3 triple play to kill a rally that had already plated one run in the second inning.
Headley fielded the sharply hit ground ball, stepped on third base and sent the ball to second baseman Lance Zawadzki, who threw on to first baseman Adrian Gonzalez, nailing Tejada by more than a stride.
"It's pretty cool, not a whole lot of guys get to say they're a part of that," Headley said. "Obviously it would've been nice to come away from here with a win, but I think tomorrow or in a couple days, I'll look back and say, 'That was pretty neat,' because guys play for 10-15-20 years and are never a part of it. And especially to do it the conventional way with a ground ball and not a line drive or something, that was pretty cool."
Garland (6-4, 2.81 ERA) took the loss but turned in his eighth quality start of the season, lasting six innings while giving up three runs.
A bunt for a hit by Jose Reyes, a throwing error by catcher Yorvit Torrealba and a bloop single by Ike Davis helped the Mets score their second and third runs in the third inning, which proved insurmountable against Niese.
"Even though they got three runs and eight hits, they didn't really pound the ball against Jon," Black said. "I thought Jon threw the ball fine. He just got outpitched."
San Diego now sits a game back of Los Angeles for the National League West lead and will have a chance to make up the difference in the nine upcoming games at home, where the Padres have posted an 18-12 record.
"We play really good baseball there, and it'll be nice to get back home, even though we'll be getting home late tonight, and our bodies will have to adapt back," Garland said. "But it will just be nice to get back home regardless of who we're playing."
Kyle Maistri is an associate reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.