Dele Alli and Gareth Bale both came into the Spurs side but neither lasted an hour, the former withdrawn among four half-time changes as Mourinho's men trailed to Lior Refaelov's 29th-minute strike.
The visiting coach turned first to Son Heung-min and then to Harry Kane - replacing Bale 13 minutes later - yet the in-form pair could not come up with a leveller despite a slightly improved second-half showing.
Again the pre-match optimism prompted by beating Burnley on Tuesday (AEDT) dissipated, with Tottenham too often this season following big victories with inexplicable setbacks.
While Spurs toiled from the outset, the Belgian Pro League leaders seized the biggest opportunity of the first half as Dieumerci Mbokani ripped the ball away from Ben Davies, raced towards goal and squared for Refaelov to control and lash into the net.
Despite the raft of Mourinho changes, Antwerp twice could have increased their advantage early in the second half.
More slack play - this time from Harry Winks - let Refaelov in, prompting a sublime recovery tackle from Davinson Sanchez, before Mbokani somehow missed the target when found by Koji Miyoshi with the goal at his mercy.
Pressure increased on the Antwerp goal, but they were soon in again on the counter, only for Simen Juklerod to fire high into the stands with only Hugo Lloris to beat.
Although that miss kept Tottenham in the match, they could not create a presentable opportunity for Son or Kane as Mourinho lost for the first time in 16 Europa League matches - including qualifiers.