Spurs travelled to eastern Germany shorn of striking options without the injured Harry Kane, Son Heung-min and Steven Bergwijn.
Leipzig captain Marcel Sabitzer struck twice in the first 21 minutes to put the tie to bed before substitute Emil Forsberg added the third late on with his first touch.
Mourinho left club record signing Tanguy Ndombele on the bench after publicly criticising the French midfielder's desire in Saturday's 1-1 draw at Burnley, but the switch to a 3-4-3 formation did little to prevent Spurs' winless streak in all competitions stretching to six games. And the visitors did not learn their lesson as Serge Aurier was caught napping by a purposeful burst from Angelino.
Spurs produced a remarkable fightback from 3-0 down on aggregate away at Ajax in last season's semi-finals to make the final for the first time in the club's history thanks to Lucas Moura's hat-trick.
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