Jan Vertonghen broke the deadlock with a header from Christian Eriksen's cross after just 12 minutes but Spurs faced several anxious moments against a lively Moldovan side and only had their lead intact at half-time thanks to a wonderful goal-line clearance by Vlad Chiriches.
Sheriff continued to cause problems in the second period but Defoe struck in the 75th minute to settle Spurs' nerves and draw level on 22 goals with Martin Chivers as the club's all-time leading scorer in Europe.
Sheriff impressed early on, pressing quickly and causing the Spurs backline problems from the outset.
The hosts managed three corners by the time Aaron Lennon saw a cross blocked by Djibril Paye for Tottenham's first in the 12th minute.
It was a set-piece that proved costly to the hosts. Erik Lamela played it short to Christian Eriksen, whose cross was nodded into the top left-hand corner with impressive control by Vertonghen.
Silence fell upon Stadionul Sheriff after the ball rippled the back of the net, although the raucous home support soon found their voice again.
Henrique Luvannor, the top scorer in the Molodovan league, broke free on goal and looked all but certain to score after rounding Hugo Lloris, only for Chiriches to remarkably clear off the line.
Kobi Moyal curled wide from outside the box as Sheriff continued to press, although that left them open to quick Spurs breaks.
Villas-Boas' side looked set to capitalise on that weakness when an Eriksen flick put Lennon through on goal, only for Vjekoslav Tomic to save the close-range drive with his legs.
A lack of match sharpness was perhaps to blame for the miss, which looked like it would prove costly when Cadu found the back of the net on the half-hour mark.
An impressive cutback from Henrique put through his fellow Brazilian to rifle home past Lloris, only for offside flag to see the goal chalked off - not that the home fans noticed, celebrating for a full 30 seconds afterwards.
The Moldovan champions were soon on the attack again, this time Ismail Isa breaking through and putting wide from an acute angle.
Not only were Tottenham having to deal with a clearly pumped-up home side but also a defensive re-jig, with Michael Dawson coming on for injured left-back Zeki Fryers after 34 minutes.
Perhaps that alteration was behind their sloppiness when dealing with a quickly-taken free-kick, which ended with the impressive Henrique swivelling on the edge of the box and striking just over.
Defoe also fired over as the half came to a close, with the England international firing straight at Tomic seven minutes after the restart.
Sheriff, though, were continuing to prove a threat, despite Tottenham dominating possession.
Lloris had to react quickly to prevent a clear run on goal for Isa, who later looked for a penalty, writhing around in pain after a strong challenge by Sandro.
The Brazilian saw a long-range strike deflected behind at the other end and a threatening Eriksen cross was well dealt with by Tomic as Spurs looked to pull further ahead.
Lennon's switch to the right flank was causing the hosts problems and the returning winger saw a 20-yard effort strike the post in the 67th minute.
Dawson got in the way of a Ricardinho drive when Sheriff pushed again, before Defoe put the tie to bed. Collecting a ball from substitute Nacer Chadli, the England striker rifled home to level with Chivers.Defoe wasted a chance to break the record soon after with what proved to be his last real chance, with Isa prodding wide late on for the hosts.
|Sheriff Tiraspol||Team Statistics||Tottenham Hotspur|
|0||1st Half Goals||1|
|2||Shots on Target||4|
|9||Shots off Target||4|
|19.5||1st Half Poss.||80.5|
|24.6||2nd Half Poss.||75.4|