"He's just not able to locate," Arizona manager Kirk Gibson said.
Lopez (5-12) allowed five runs on nine hits in just 4 1/3 innings. Earlier this year at PETCO, he allowed six runs on six hits, four of which were homers.
"Not much to say," Lopez said. "I've been working. There's not much I can do, I just have to keep myself positive and move forward and just do better next time."
It was the long ball that hurt him again Tuesday as he allowed a pair of two-run shots.
The first came from Will Venable in the second when he golfed a low pitch and hooked it into the right-field bleachers.
"A little slider down," Venable said. "He's a guy that's not going to beat with you with the fastball, so he's going to try to do some other things, especially when you're ahead in the count. I like the slider, he ended up leaving one over the plate, and I was able to put a swing on it."
That put the Padres up 2-0 and they would double their lead in the fourth.
With two outs in that frame, Lopez walked Venable and then gave up a towering homer on the first pitch to Chris Denorfia.
"On those two home runs you don't like to see those pitches in those situations," Gibson said.
Meanwhile, while the D-backs were able to get baserunners against San Diego starter Clayton Richard, they were unable to get them across the plate.
It was the second straight game the D-backs had been held scoreless. Arizona has not scored since the sixth inning of Saturday's contest with the Rockies.
"It has been two really tough days, we just have to keep grinding," catcher Miguel Montero said.
"Got a couple of guys on and they popped two on us and we haven't scored in two games, so that's not a very good formula," Gibson said.
Richard (12-5) allowed three hits and walked five over six innings, but pitched his way out of jams. The D-backs left seven runners on base in those innings.
The D-backs managed to get just one leadoff hitter on against Richard, which helped him in wiggling out of trouble.
"It was tough because when we got a man on it was with one out or two outs, so he had a chance to get out of a jam quick," Montero said. "And then he works really fast so he keeps you off balance, it was like get the ball throw the ball."
For much of this season Lopez has been a workhorse for the D-backs, pitching deep in games, but he has not been able to go past five innings in his past four starts and two of his past three have been struggles. Despite that, and the fact that he is at 161 innings for the year -- a total he has not reached since 2006, Lopez says his recent struggles are not a result of fatigue.
"Not really," Lopez said. "Honestly, I feel good out there, I don't feel tired."
Gibson said he didn't know if Lopez was running on empty, but he does know the results have not been there.
"He has not thrown the ball like he did early in the year for sure," Gibson said.