Tottenham slipped to a first away defeat since July after a mistake by Ben Davies helped Royal Antwerp leapfrog their Europa League opponents to go top of Group J.
Davies, making his 200th Spurs appearance, was easily dispossessed by Dieumerci Mbokani, whose pass allowed Lior Refaelov to smash past Hugo Lloris.
Flat and uninspired, Spurs struggled to carve out chances and Jose Mourinho made four changes at the start of the second half in an attempt to inject some urgency into his side.
But it could have been worse for Tottenham, Mbokani somehow blazing over from three yards out before Harry Kane was sent on in an attempt to rescue the game.
Simen Juklerod also missed a fine chance for the hosts after being sent clean through as Spurs failed to score for the first time since the opening weekend of the season.
Mourinho's side are three points behind Royal Antwerp in Group J after two games, level on points with Austrian side LASK, who beat Ludogorets 4-3.
Lacklustre Spurs fail to impress Having embarked on a 10-match unbeaten run since losing at home to Everton on the opening weekend of the season, this was as bad as Spurs have performed in a long time.
Mourinho showed his displeasure by making a string of changes at the break against a well-organised side.
Dele Alli was handed his first start since 24 September but is still to finish a match this season after being hauled off at half-time in two of the three games he has started.
Alli at least created a chance for Carlos Vinicius before he was replaced, former Manchester United full-back Ritchie de Laet producing a fine challenge before the Spurs player could shoot.
Netherlands winger Steven Bergwijn and Argentine midfielder Giovani lo Celso did manage attempts before the interval but both were comfortably dealt with by keeper Jean Butez.
Kane replaced Gareth Bale, who has also yet to complete 90 minutes since rejoining on a season-long loan from Real Madrid.
The Wales forward is still trying to reach peak fitness after missing a number of games but there was little creativity from the four-time Champions League winner in Belgium.
Kane and Son Heung-min have scored 20 goals between them this season but even their introductions from the bench failed to ignite the team, Spurs unable to test the home keeper at all in the second half.
'Poor performance, poor result' - what they said Tottenham boss Jose Mourinho: "Blame me because I am the boss and it is my responsibility who plays and I am the one to blame.
"But I have to admit that the game confirmed to me a few things, opened other question marks and will help me in the future with my decisions.
"I'm also learning every day.
The performance was poor and the result is poor.
" Mourinho's first Europa League defeat since 2016 - the stats This was Jose Mourinho's first defeat in a Europa League game since November 2016, ending a 12-match unbeaten run for the Portuguese manager in the competition.
Spurs have never won away to Belgian opposition (P6 D2 L4), losing on each of their past three visits.
Royal Antwerp are the first Belgian side to beat English opposition in European competition since KAA Gent beat Tottenham in the Europa League in February 2017.
What's next? Tottenham are back in action on Sunday when they host Brighton in the Premier League (19:15 GMT).