"I didn't realize it went over the fence," Moss said. "I thought it was going to be a sacrifice fly. Then I saw it bounce around and was shocked. That's not a home run at night. Being a day game, the ball carries better."
Jed Lowrie had three hits and drove in a run for the A's, who have the best record (63-38) in baseball and are a season-best 25 games over .500.
Chris Carter hit a home run for the Astros, who fell to 2-4 since the All-Star break.
Samardzija (2-1) gave up a leadoff single to Jose Altuve and then retired 10 straight before Carter's 20th home run put Houston on the board. He did not walk a batter and struck out six.
He retired 12 of 13 following Carter's blast. Carter was the lone Astro to get past second base against Samardzija, who received a combined 13 runs of support over his final six starts with the Cubs.
"I was just trying to get quick innings and not keep the defense out there very long," Samardzija said. "I wanted to keep them in hitting rhythm. When you get a lead like that, you just take a deep breath."
Samardzija was 2-7 with the Cubs despite a 2.83 ERA. He entered with the third-lowest run support in the majors at 3.05 runs per outing.
"I'm having a lot of fun playing here," Samardzija said. "I just attacked the zone and threw a lot of fastballs."
Scott Feldman (4-8) lost his straight start, lasting 5 1/3 innings. He allowed six runs and nine hits, walking five and striking out four.
"He battled but at the same time they did a tremendous job of hitting with runners in scoring position," Astros manager Bo Porter said. "That's pretty much what was the difference in the ballgame."
Feldman allowed at least six runs for just the third time this season but for the second time in three starts. He has allowed 16 runs and 27 hits over his last 17 2/3 innings.
"It was a battle for him all day," Porter said. "Early in the game he really had his breaking ball working, and they started laying off and made him come back into the zone."
The A's were ahead 4-1 entering the sixth inning when Moss hit his third grand slam of the season.
"You want to cash them in with runners on base," Moss said. "It was a situation where the guy had to make a good pitch and I hit it. I had the bases loaded in the at-bat before and ended up hitting a weak grounder to first."
Donaldson and Derek Norris, who had three hits, each drove in runs in the third. Sogard scored on a wild pitch. Crisp's sacrifice fly in the fourth put the A's ahead, 4-1.
RHP Jim Johnson was designated for assignment before the game, ending a short, tumultuous relationship with the A's fans, who have booed him since opening day. ... A's OF Yoenis Cespedes (sprained right thumb) could return to the starting lineup on Friday. ... A's INF Alberto Callaspo (right hamstring strain) is scheduled to begin a rehab assignment on Saturday. .. RHP Jason Hammel (0-2, 9.00) is scheduled to make his third start for the A's against the Rangers in Texas on Friday. ... LHP Dallas Keuchel (9-6, 3.29) starts for the Astros at home against Miami, which begins a 10-day, 10-game homestand, the longest of the season. ... Samardzija improved to 21-3 lifetime when receiving at least three runs of support.