The strikers, past and present, are now neck and neck on 22 goals, with Defoe scoring our second of the game after Jan Vertonghen headed us into a first half lead in a game that Sheriff will look back on with some disbelief over the fact that they did not contribute to the goals tally on the night.
Andre made seven changes to the side which defeated Aston Villa at the weekend, with Kyle Naughton, Zeki Fryers, Mousa Dembele, Aaron Lennon, Christian Eriksen, Erik Lamela and Defoe all drafted into action in Tiraspol on a fresh misty evening.
It was Lennon's first start after picking up an injury on the season's opening day at Palace.
Sheriff were calling the shots in the opening stages, looking sharp and purposeful until the wind was taken out of their sails on 11 minutes when a corner from Eriksen was nodded home with the minimum of fuss by Vertonghen, with home keeper Vjekoslav Tomic rooted to the spot.
The team in yellow did respond and Luvannor Henrique burst clear a few minutes later and managed to round Hugo Lloris before directing a shot goalward. However, Vlad Chiriches was alert to the situation and slid across to clear superbly.
Eriksen then sent Lennon through one on one with the keeper, but Tomic used his feet to deny the returning winger from a comeback goal.
Cadu did smash into the net on 30 minutes and the stadium erupted, but joy was short lived due to the raising of a flag for offside. Ismail Isa then broke through to the left of the area but shot wide of Lloris' left hand upright.
Michael Dawson was introduced on 34 minutes for the injured Fryers, with Chiriches switching to right back, Naughton left, with Vertonghen and Dawson completing the back four in the middle.
Henrique squandered another opportunity to level after being picked out by Isa in the area before Defoe had the chance to level our European goalscoring record just on the break but couldn't control Eriksen's measured chip into the danger area.
In truth Sheriff could consider themselves unfortunate to be losing when half-time came along.
Eriksen teed up Defoe in the first movement of note in the second period, with the striker's tame shot fairly easily fielded by Tomic, while Lloris was his usual speedy self in racing off his line to deny Isa.
Nacer Chadli replaced Lamela on 61 minutes and five minutes later Lennon hit the inside of the post after a typical dash forward.
Dawson then diverted a Kobi Moyal shot wide via his heel as Sheriff once again threatened strongly on the break.
Their resolve would have been dented somewhat by what happened next. Chadli strode across field before slotting towards Defoe, who unleashed a shot from 25 yards that defeated Tomic in the Sheriff goal and flew into the top corner.
Lewis Holtby took over from Sandro in midfield before Isa should really have scored again after bursting through but, put off by Lloris' speed off his line, shot wide.
Possession stats saw us with a 76-24 hold on the game, but our fifth win in five in the Europa League and third in three in Group K proved a real test.
FC Sheriff: Tomic; Balima, Metoua, Samardzic, Paye; Moyal (Furdui, 69), Stanojevic; Ricardinho, Cadu (Fernando, 84), Henrique; Isa (Paireli, 88). Subs: Stajila, Scripcenco, Celstino.
Spurs: Lloris; Naughton, Chiriches, Vertonghen, Fryers (Dawson, 33); Dembele, Sandro (Holtby, 76); Lamela (Chadli, 61), Eriksen, Lennon; Defoe. Subs not used: Friedel, Holtby, Sigurdsson, Adebayor, Soldado.
Yellow cards: FC Sheriff - Stanojevic; Spurs - Chiriches.
Goals: Spurs - Vertonghen (12), Defoe (75).
Referee: Mr L Liany (Israel).