"Obviously this will be a blow for us given the goal threat that Thomas has been here," said the 50-year-old coach, after his player was booked for a handball and must now sit out their match against the European champions.
"But we have players who can replace Thomas and we will manage that," he said.
Mueller, who only won his first international cap in March in a friendly against Argentina and was one of Loew's last call-ups for Germany's youngest World Cup squad since 1934, has been crucial to their fast-paced style of attacking football.
A somewhat harsh referee decision means, however, he will miss the biggest match of his young career.
But Loew's words, only a few days before their sensational quarter-final victory against the much-fancied Argentines, now seem to have been prophetic.
"I do not try to find a tactic to fit the players that I have," he had said earlier this week. "I want players who can apply my tactics and vision of football, what I want to see on the pitch and this is how I select them."
It is this concept that has created a well oiled attacking machine that marches on despite any injuries or suspensions. There seems to be a seamless transition when players replace each other.
The injury of then captain Michael Ballack that ruled him out of the World Cup was absorbed almost immediately.
Striker Miroslav Klose was suspended for their final group game against Ghana but his absence was not felt as Cacau slipped into his role with Germany winning 1-0.
Left back Jerome Boateng has replaced Holger Badstuber after the first two matches with the backline now looking stronger than ever.
The same will no doubt happen against Spain with Stefan Kiessling being drawn out to the wing or even Mario Gomez slipping into Mueller's role.
Cacau, fit after an abdominal muscle strain, is also an option despite being a more centrally active forward.
While playing with only one out-and-out striker until now, Loew has repeatedly said a two-pronged attack is always an option for his extremely flexible team.
He seems more interested in wanting to keep his players' feet firmly on the ground.
"We must now emotionally not go over the top,"" he said. "Until now I have never got that impression. Obviously the joy was there in the changing room but all players were already thinking ahead."
"We are in the semis but the tournament is still ongoing. It is important to focus on the next job at hand," Loew said.