The result means Spurs cannot progress from Group E and need a point against CSKA Moscow at Wembley next month to finish third and qualify for the Europa League.
Spurs stopper Hugo Lloris denied former Manchester United and Chelsea striker Radamel Falcao’s spot-kick in the first half and made a number of superb saves but second-half goals from Djibril Sidibe and Thomas Lemar gave Monaco a deserved victory.
Harry Kane offered Tottenham temporary hope when he equalised from the penalty spot but the visitors simply never found the spark required to resurrect their faltering fortunes in Europe.
Monaco, meanwhile, are now guaranteed to go through as group winners with Leverkusen, who had earlier drawn 1-1 with CSKA.
Pochettino took a gamble by leaving out Jan Vertonghen and replacing him with the largely out-of-favour Kevin Wimmer – a move perhaps reflecting the importance of Saturday’s match against Chelsea, when Vertonghen will be the last available option at left-back with Danny Rose serving a domestic suspension and Ben Davies out injured.
Dele Alli, however, was passed fit – although with his troublesome left knee heavily strapped – and there was also a first Champions League start for 20-year-old academy graduate Harry Winks, who had marked an impressive display against West Ham with a goal three days earlier.
It meant a 4-3-2-1 formation from Pochettino, his third different system in as many matches and symptomatic of the Argentinian’s dissatisfaction with his side’s recent form.
Son Heung-min could have given Tottenham the perfect start when he was played through one-on-one by Alli but as he tried to go around goalkeeper Danijel Subasic, the South Korean took a heavy touch and the chance was gone.
That was as good as it got in the first half for the visitors, who should have fallen behind five minutes later when Victor Wanyama and Eric Dier both took wild swings at the advancing Fabinho, with Dier connecting to concede a penalty.
Falcao has scored five goals in his last three matches but was unable to capitalise as Lloris guessed correctly by diving low to his right and palming the ball away.
Spurs were rattled. They were careless in possession and frantic at the back, as a rampant Monaco forced mistakes and broke through almost at will.
Lloris was called into action again to save Benjamin Mendy’s fizzing finish and then a feeble follow-up from Valere Germain, who was then guilty of failing to take advantage of a free header at the back post, instead heading straight into the midriff of Wimmer.
Germain was a constant menace in the channel between Wimmer and Rose, and he fired another shot narrowly wide of Lloris’ far post before Spurs traipsed off at half-time, relieved still to be level.
Whatever Pochettino said during the interval, there was little change after the restart as three goals flew in during a lively four minutes.
First, Sidibe headed home from close range after Mendy had left Winks for dead out wide but Tottenham were level almost immediately, as Alli was pulled back by Kamil Glik and, after a long hesitation, Dutch referee Bjorn Kuipers pointed to the spot.
Kane converted, his low shot too powerful for the outstretched hand of Subasic – but no sooner had the visitors equalised than they found themselves behind again.
Monaco needed only four passes from kick-off to unlock their opponents and again it was both full-backs involved, this time Sidibe supplying the cross for Mendy to drive home at the back post. Pochettino swivelled on his feet in frustration.
If Spurs still harboured hopes of a comeback in the latter stages, it was only due to the brilliance of Lloris, who pulled off a superb reaction save to deny Glik from six yards and soon after was flying through the air again to stop Falcao’s stinging finish.
In between, Dier saw a header blocked on the line but while Pochettino introduced Christian Eriksen, Vincent Janssen and Moussa Sissoko from the bench, his side never looked like repeating Saturday’s late drama against West Ham.
Alli volleyed wide at the back post in the 86th minute in what was Tottenham’s last chance. After taking five years to get back into the Champions League, they are out of it within three months.