Toffees boss David Moyes handed a start to Nuno Valente at left-back, while record signing Yakubu was given a lone role up front, with Anichebe and James McFadden among the substitutes.
Everton almost made a dream start as Mikel Arteta's shot was beaten out by Jaromir Blazek and Tim Cahill's follow-up came back off the upright, with the keeper getting a vital touch.
Ten minutes in an error from Joleon Lescott allowed Ivan Saenko a run on goal, but Tim Howard was out bravely to gather at the forward's feet at the edge of the area.
Arteta and Leon Osman combined superbly in the 17th minute, but the latter's cross was just too strong for the arriving Cahill at the far post.
Peer Kluge fired narrowly wide as Nurnberg pressed, before Howard had to tip away a powerful Dominik Reinhardt drive from 18 yards out.
A goalmouth scramble shortly before the break almost saw Everton break through, but Blazek was down to grab the loose ball near to the goal-line.
Straight after the restart Marek Mintal threatened for the home side, with Howard standing strong to make the block.
Arteta then threatened at the other end as his drive just before the hour mark swerved at the last moment and Blazek needed two attempts to gather.
Both sides were finding it difficult to carve out clear chances and 15 minutes from time Yakubu gave way for Anichebe.
The young striker made his mark eight minutes from time as he won a penalty for a foul by Glauber and Arteta stepped up to confidently bury the spot-kick, sending Blazek the wrong way.
Anichebe then completed his super-sub display as he out-muscled Jaouhar Mnari down the right and slid the ball under Blazek at his near post to make the final score 2-0.