Andre Silva scored twice as Sevilla comprehensively defeated Champions League holders Madrid at the Ramon Sanchez Pizjuan midweek.
Madrid were no match for Sevilla away from home – the Spanish capital club suffering their first LaLiga defeat of Lopetegui's reign.
Reflecting on the result in Seville, head coach Lopetegui told reporters: "Our problem was that Sevilla were clearly better than us, particularly in the opening stages.
"They netted twice and were very clinical early on. We were second best in the first half and in the second we were more evenly matched but we missed a couple of big chances that killed any hopes we had. It was a poor performance on our part and Sevilla are deserved winners."
Madrid thought they had pulled a goal back in their hopes of a comeback early in the second half, however, Luka Modric's goal was disallowed by VAR.
"The idea was to press high but it didn't come off like we'd hoped and we paid for it, particularly at the beginning. It'd be opportunistic to say we didn't prepare for the game adequately but it looks like that was the case," continued Lopetegui, whose Madrid must pick themselves up for Saturday's derby against Atletico Madrid.
"Neither the players nor the coach were at their best in the first half. If the goal early in the second half had stood, we would have had a chance."
LaLiga champions Barca are ahead of Madrid on goal difference after six rounds.
"The league is a marathon and will pose real challenges," Lopetegui said. "We need to prepare for the next game well.
"This kind of thing happens in LaLiga and it will happen again, now we have to prepare for an important, challenging game at home in the next three days. Tomorrow we will get up and prepare for the next game as best we can."