Andre Villas-Boas' men suffered some nervy moments in Tiraspol despite dominating possession, though struck twice to record their fifth successive win in Europe this season
The north Londoners took an early lead with their first meaningful attack of the game, as Jan Vertonghen headed in at the far post following a whipped delivery from former Ajax team-mate Christian Eriksen.
Sheriff frequently broke Spurs' lacklustre offside trap, keeping goalkeeper Hugo Lloris busy, but the Premier League side wrapped up victory when Jermain Defoe lashed the ball into the top corner from range.
Spurs boss Andre Villas-Boas rotated heavily, making seven changes from the side that beat Aston Villa, with Defoe and winger Aaron Lennon - on the comeback trail following a foot injury - the most notable inclusions.
Sheriff started well but would have been cursing their luck as the north Londoners took the lead in the 12th minute; Erik Lamela took a short corner to Eriksen, and Vertonghen rose above Miral Samardzic to head in the Dane's curling cross.
Sheriff should have responded just three minutes later, but after rounding Tottenham goalkeeper Lloris, Henrique Luvannor was denied by a fantastic goal-line clearance from Vlad Chiriches.
Kobi Moyal shot wide following another quick counter-attack a few minutes later, before Lennon wasted a one-on-one opportunity, shooting at the legs of Sheriff goalkeeper Vjekoslav Tomic.
That was a rare chance in a sustained spell of Sheriff dominance, though, as Ismail Isa had a goal ruled out for offside before the same player curled an effort just wide with the Tottenham struggling to contain the home side.
Spurs were forced to re-shuffle their defence after left-back Ezekiel Fryers was forced off with a groin injury just after the half-hour mark, but they continued to struggle with the pace and dynamism of Isa and Luvannor, with the latter shooting just over on the turn seven minutes before the break.
After a slow start to the second half, Lennon saw a 20-yard driven effort hit the far post, while at the other end, substitute Michael Dawson was in the perfect position to block a goal-bound Ricardinho strike.
Tottenham sealed the victory in the 75th minute, though, as Defoe fired in from 25 yards thanks to a wicked deflection that deceived Tomic. The strike, the England international's 22nd in Europe, equalled Martin Chivers' club record.
Defoe almost scored again moments later, poking just wide of the far post, while Isa wasted a chance to give the hosts a lifeline as Tottenham maintained their perfect start.