The Germany duo have struggled in recent weeks and both were left on the bench for Saturday's home clash with Rayo Vallecano.
Ozil appeared after just 29 minutes, replacing the more defence-minded Lassana Diarra with Madrid 1-0 down, and played a key role as Jose Mourinho's men ran out 6-2 winners.
Khedira, sent off the previous week at Levante, came on approaching the hour mark.
Ozil, in particular, was impressive in his first year in Spain and Karanka, again standing in for the suspended Mourinho, is confident both he and former Stuttgart man Khedira will come good once more, starting on Tuesday night in the Champions League clash with Ajax.
"They are players who were important to the team last season and I'm sure this will also be the case this year," he said.
"Players always go through good times and some not so good times. Ozil demonstrated when he came on against Rayo what a good player he is.
"Sami is coming back from an injury and will certainly be a major player for us. "
Summer signing Hamit Altintop has been included in the 21-man squad but Karanka hinted the Turkey international was not yet fit enough to make his first appearance since his switch from Bayern Munich.
"Altintop has been working well and he needs to be with the team and to get used to the dynamics of the group. This will be good for him," he said.
Ajax made the same trip to Madrid last September and were beaten 2-0 although the scoreline should have been more emphatic given the hosts' superiority.
Defender Toby Alderweireld is confident the Amsterdammers will have a completely different mindset this time round.
He told AD Sportwereld: "We were just pleased to be there (last year).
"Now we are going there to get a good result. We should not be fazed by Real and must regard this as a normal game."
Midfielder Siem de Jong struck a more cautious note.
"They are a great team," he said. "We have to work out when to put pressure on and when to retreat. That is something you can only do during the game.
"Last season we let them come at us. We also need to go forward."
Ajax are third in the Eredivisie following Saturday's 1-1 draw with title rivals FC Twente.