La Roja suffered their first qualification defeat in 37 matches on Thursday when they lost 2-1 in Slovakia.
Now, Del Bosque has promised sweeping changes to his XI.
"We planned to make changes for Luxembourg before the match against Slovakia and defeat doesn't change our idea," he told AS.
"We believe in making five changes and barring unforeseen circumstances, that's what we'll do."
Iker Casillas is expected to continue in goal despite ongoing criticism of the Real Madrid stopper.