Los Blancos opened the defence of their Champions League crown with a 3-0 win over Roma on Wednesday night.
There is, though, little time to regroup as Espanyol head to the Bernabeu for the start of a hectic run of fixtures which also includes the Madrid derby at the end of September.
— LaLiga (@LaLigaEN) September 19, 2018
Lopetegui confirmed he would look to rotate the side once again to make sure everyone stays fresh for the challenges ahead.
"That's the way the fixtures fall. We've got seven games in three weeks. It's normal at a Champions League team and a club like Real Madrid," Lopetegui said.
"We have to go into it naturally and make the best decisions in each game, knowing the strength in depth we've got at our disposal, more than ever."
The Real Madrid coach added at a press conference: "We can only take it game by game.
"We have to focus on each different situation and make the best decisions, also depending on the opposition. Squad rotation is vitally important.
"We always make the decisions we believe to be in the best interests of the team at any given moment.
"Football is not about a starting XI – there are 14 players involved in every game. In a squad that aspires to win everything, every single player is important."
Defender Dani Carvajal will not feature after missing training, due to an unspecified minor issue, but Lopetegui expects him to be available again for the trip to Sevilla on Wednesday night.
Goalkeeper Keylor Navas came back into the side for the midweek Champions League fixture.
Lopetegui, though, is not about to declare who is his number one, with Thibaut Courtois having played in the previous two LaLiga games following a big-money summer move from Chelsea.
"They are training brilliantly and competing very well. There's nothing forced about the situation, it's clear from the inside even if from the outside it may not look it," the Real Madrid coach said.
"Everything in football is simpler on an internal, professional level than people want to make out."
Espanyol head to Madrid in fourth place, just three points behind Los Blancos. Lopetegui is in no doubt about the scale of the challenge facing his side.
"It is the toughest test we've faced so far this season at the Bernabeu," he said.
"They are a much-improved team and are well-rounded in several aspects.
"They've had all week to get ready for this game and we'll be forced to play very well if we want to win. "
Espanyol midfielder Esteban Granero feels confidence is high within the squad.
"We cannot slow down. We have the ability to play well, compete and win big teams," he said, quoted on the club's official website.
"It will be a clash of two good teams which will fight to win. It will not be easy for either of us."