Andre Villas-Boas' men have lost just two of their last 22 European games at White Hart Lane, and comfortably beat the Moldovan side 2-0 when they met in Tiraspol last month.
A repeat of that result will put Tottenham in the last 32, regardless of the result between Tromso and Anzhi Makhachkala in Group K's other fixture on Thursday.
Defoe is the joint-top scorer in the competition proper with four goals in three starts and will be eyeing another chance after seeing Roberto Soldado fire a blank against Everton in Sunday's 0-0 Premier League draw.
|7/1||Tottenham are 7/1 with Coral to win the Europa League|
"Would we look to play some of the young players? There is that possibility, yes, and, if we ensure qualification, first place, we will probably do that," he told reporters.
"I don't want to step too far ahead because we need to push the boys for that deserved start, but, as soon as we achieve it, we can look at it as an opportunity to throw them in to a senior game."
Hugo Lloris' spot in goal could be up for grabs after the Frenchman was knocked unconscious at Goodison Park at the weekend.
Lloris was controversially allowed to continue playing after insisting he was fine, but Brad Friedel is waiting in the wings for his second outing in this season's Europa League.
The likes of Nacer Chadli, Christian Eriksen and Etienne Capoue will be hoping for places in Villas-Boas' XI after being limited to substitute appearances in the league recently.
Sheriff required an 84th-minute winner from striker Ismail Isa to seal Saturday's 3-2 triumph over out-of-form Rapid Ghidighici and maintain their seven-point lead at the top of the Moldovan National Division over Costuleni and city rivals Tiraspol.
The Bulgarian had been on the pitch for just seven minutes, having entered the clash as an injury doubt, but head coach Veaceslav Rusnac has a fully fit squad to choose from for Thursday's fixture.
Rusnac is determined to take something from the game as Sheriff look to keep the pressure on second-placed Anzhi, whom they sit two points behind.
"By now everyone is healthy and ready to take the field," he said. "We are not going to London just to have a regular game on the field. We are coming to get points because we want to play in Europa League in spring."