Jose Mourinho evidently felt the match would be less testing than the 2-1 win in Bulgaria and rested captain Hugo Lloris, as well as Kane, Lo Celso and Lucas Moura in Skopje.
Given Tottenham's packed schedule, which Mourinho has described as "inhuman", the manager would have wanted his side to build on Erik Lamela's fourth-minute goal and see out the game with minimum effort.
But his profligate players missed a host of chances and were pegged back Valmir Nafiu's second-half screamer.
Mourinho called for the calvary on the hour, introducing Kane and Lo Celso before Lucas, and Spurs eventually saw out the tie in relative comfort after goals by Son and Kane.
Spurs will face Maccabi Haifa of Israel in a final Europa League play-off next Thursday, this time at home, and he will hope it is not as much of a battle as the trips to the Balkans.
Dele status no clearer after frustrating return
Jose Mourinho laid down the gauntlet for Dele Alli, challenging the 24-year-old to perform in North Macedonia before restoring him to the starting XI after two matches on the sidelines.
Dele lasted an hour – 15 minutes longer than the opening-day defeat to Everton – and was hooked for Kane with Spurs desperately needing a goal. The substitution hardly suggested Mourinho's faith in Dele had been restored and the midfielder's status at the club seems no clearer.
Dele looked like a player suffering from a lack of match sharpness in the early exchanges, more than once failing to find a teammate with an ambitious pass, but he did not appear short of motivation, constantly demanding the ball.
His big chance game midway through the first half when his close-range shot was saved by the Shkendija goalkeeper. Had he scored, it may have been an important moment in restoring his confidence but as it was, this will go down as another frustrating evening for Dele.
Ndombele, Lo Celso offer glimpse of the future
Mourinho gave Ndombele and Lo Celso a half each in the 5-2 win at Southampton on Sunday, as they continue to work their way to full fitness.
Since splashing out on the duo a year ago, there have been precious little opportunities to see them side-by-side in the midfield, with Ndombele falling out of favour last season after Lo Celso had forced his way into the team.
With the Frenchman seemingly now back in Mourinho's good books, and completing a rare 90 minutes here, and Lo Celso a 60th-minute substitute, the pair offered a glimpse of what a future Spurs midfield could look like – likely with Pierre-Emile Hojbjerg, who missed the game through injury.
Ndombele was a little erratic but nonetheless showed all his usual touches of unconventional excellence, while Spurs sorely missed Lo Celso's drive before his introduction. It increasingly feels as they cannot do without the Argentine. One casualty of Ndombele's comeback could be Harry Winks, who was disappointing in the centre of midfield and made way for Lo Celso on the hour.