Upton hit a solo homer with two outs in the eighth inning off Greinke to give the Padres a 2-1 victory over the Los Angeles Dodgers on Saturday night.
Upton has an excellent track record against the 2009 American League Cy Young Award winner, and it showed in the eighth.
"That's what makes the game fun, when you are in pressure situations," said Upton, a two-time all-star. "I think you ask most guys and they enjoy those situations."
Upton connected on a 3-2, hanging slider into the stands in left field for his ninth game-winning RBI this season.
"It was my first bad slider I threw all day," Greinke said. "When you make a mistake to him, he does damage."
Catcher Yasmani Grandal, a former Padre, said Greinke made "one mistake and he made it to the guy we shouldn't have. He has been the heart of their team all year."
Upton leads San Diego with 13 homers and 39 RBI. He has a .370 career batting average (10 for 27) with two homers against Greinke.
"These guys thrive on these moments, both ways," Padres manager Bud Black said. "Two high caliber players going toe to toe."
Dodgers manager Don Mattingly challenged the home run, contending a fan may have reached over the wall trying to catch the ball. But the call was upheld in 42 seconds.
Greinke, who came in 5-0 with a 1.53 ERA against San Diego in 10 career starts, had pitched well into the eighth inning.
The right-hander had allowed just one run and seven hits and had retired the first two batters of the inning before Upton homered.
Ian Kennedy matched Greinke through seven innings, allowing one run and four hits with four strikeouts and one walk. After breaking a string of four consecutive defeats with a 9.31 ERA, Kennedy turned in his third straight strong start.
The loss snapped the Dodgers' four-game winning streak.
The lack of support for Greinke was nothing new for the right-hander. It was the sixth time in seven starts that Greinke has received two or fewer runs of support.
Despite the superb effort, Kennedy is winless in his last 12 starts against the Dodgers, going 0-7.
Grandal hit his seventh homer of the season leading off the third to tie the score at 1-all.
WHERE AM I?
San Diego's Yonder Alonso, who has started 339 games at first base in the course of six seasons, made only his second career start at third base. When the left-handed swinging Joc Pederson led off the game, San Diego employed a shift on the right side of the infield and had Alonso stationed on the grass in short right. Alonso's brother-in-law is Baltimore's smooth-fielding third baseman Manny Machado.
BRING ON THE DODGERS
Saturday night's attendance of 43,525 was the Padres' eighth sellout of the season at Petco Park, and the fourth with the Dodgers in town. In Los Angeles' only other appearance here this season, the teams drew a total attendance of 127, 987, the third-highest total for a three-game series at Petco.
RARE GREINKE LOSS VS. NL WEST
Since joining the Dodgers in 2013, it was a rarity for Greinke to lose to an NL West team. He is 22-3 with a 2.07 ERA against division opponents.
Dodgers: LHP Paco Rodriguez (left elbow strain) will begin a rehab assignment on Monday with Single-A Rancho Cucamonga. .. RHP Brandon League (right shoulder impingement) will make his third rehab appearance on Monday or Tuesday. .. INF/OF Scott Van Slyke (back inflammation) is scheduled to play the next three straight days for Rancho Cucamonga.
Padres: In his first start in more than three years, LHP Corey Luebke threw 14 pitches in one scoreless inning Saturday night for Single-A Lake Elsinore. Luebke, who has undergone two Tommy John operations, pitched for the first time since April 2012. ... RHP Josh Johnson (Tommy John surgery) will throw a simulated game in San Diego on Monday.
Dodgers: RHP Mike Bolsinger (4-1, 2.08 ERA) has been tough on all opponents this season, including San Diego. In his only start against the Padres, the righty limited them to one hit with eight strikeouts in eight scoreless innings of a 2-0 win on May 23.
Padres: RHP James Shields (7-0, 3.79) remains the only pitcher in the majors who has at least five wins and 10 or more starts with a loss. The 7-0 start is a personal best for Shields.
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