The 20-year-old winger has wreaked havoc in his first major tournament, scoring his fourth goal in Germany's 4-0 demolition of Argentina on Saturday to advance to the last four but coach Low knows no one in his young squad is irreplaceable.
"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.
Muller, 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.
But Low'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."
The same will no doubt happen against Spain with Stefan Kiessling being drawn out to the wing or even Mario Gomez slipping into Muller's role.
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," Low said.
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