Mejias-Brean, 28, who made his big league debut on Sept. 4, hit a two-run homer with no outs in the 10th inning and the Padres beat the Arizona Diamondbacks 6-4 Sunday.
"This whole month has been amazing, just to be up here and to have that to add on top of my first hit and first home run the last couple of days, words can't describe what I'm feeling right now," said Mejias-Brean, who had his first multi-hit game with three.
He homered off Yoan Lopez (2-7) on a 1-1 pitch for his second overall and his first walkoff homer. Greg Garcia was aboard on a leadoff double.
"I was trying him over. He's at second, trying to get a team at-bat going and just kind of happened he hung me a slider and I got it."
Mejias-Brean earned the promotion after putting up big numbers at Triple-A.
"I know the guys in there are going nuts over it," Barajas said.
"Up until this year, he did not have an opportunities," Barajas said. "To see a guy who was labeled Doing everything the right way, absolute professional,' get the opportunity, and take advantage of it and shine a little bit, it's been an honor to see him go out there and play, actually."
Barajas, a former big league catcher who had been in his first season as Padres bench coach, said his first win "was great. It's only for these eight games, but it still means something. I enjoy this opportunity. I'm trying to take advantage of it. I'm trying to help these guys win baseball games. They were probably more excited than I was. I got a beer shower and all that good stuff. I had to do a costume change before I came out here. It was fun. It was awesome."
Barajas was promoted Saturday after Andy Green was fired. The Padres lost Saturday night, 4-2.
The Padres avoided a three-game sweep and pushed the Diamondbacks closer to elimination from the wild-card race. Arizona is six games back of the Washington Nationals and Milwaukee Brewers, who are tied for the two NL wild cards.
Matt Strahm (6-10) pitched a perfect 10th for the win.
Padres center fielder Manuel Margot leaped at the fence to rob Christian Walker of a two-run home run to end the seventh.
The Diamondbacks took a 4-0 lead in the second against Garrett Richards but were held in check by San Diego's bullpen.
"When you don't close out a deal and you're playing a good baseball game for the first half and get a little inconsistent, it's a little bit frustrating," manager Torey Lovullo said. "That's what we're dealing with right now. It was a tough loss to absorb, especially watching the way things unfolded in the 10th inning. I keep saying it, no matter what the circumstances, we need to regroup the troops and be ready to play a clean baseball game tomorrow."
Arizona lefty Robbie Ray struck out 10 in 5 1/3 innings, but also allowed four runs and three hits, with four walks.
He said the strikeouts were "nice; it just stinks that we lost today. It's tough to kind of step back and evaluate it. Anytime we lose, looking at stuff like that is not a priority."
Richards didn't get out of the second inning in his Petco Park debut after allowing four runs in the span of seven batters. Walker drew a leadoff walk and San Diegan Adam Jones hit a two-run home run with one out, his 16th. Nick Ahmed followed with a triple and scored on Carson Kelly's single. After Robbie Ray's sacrifice, Abraham Almonte hit an RBI double.
Richards walked Josh Rojas and was replaced by Javy Guerra, who got Eduardo Escobar to ground out on his first pitch to end the inning.
San Diego's Ty France hit a two-run homer in the fourth off Ray, his seventh.
The Padres tied it in the sixth, when Ray put two runners on before striking out Luis Urias and then making way for Matt Andriese. He got the second out but then allowed an RBI single by rookie Seth Mejia-Brean and an RBI double by pinch-hitter Francisco Mejia.
Richards, who made his second start in his return from Tommy John surgery, allowed four runs and four hits, struck out two and walked two.
Diamondbacks: LHP Alex Young (7-4, 3.27) is scheduled to start the opener of a three-game home series against the St. Louis Cardinals on Monday night.
Padres: Rookie RHP Ronald Bolanos is scheduled to start Tuesday night's opener of the final home series, against the Los Angeles Dodgers.
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France jacks one that cuts the lead in half
Ty France drives one to deep right field and over the wall for his seventh home run of the season and cuts the D-backs' lead in half.