On an uncomfortable night for the Gunners boss, Saka was forced off on 34 minutes, shortly after Adrien Thomasson's fine strike cancelled out Gabriel Jesus' unerring finish into the bottom corner, and in his absence the visitors limped to a deserved defeat.
Elye Wahi finished an incisive Lens attack in the 69th minute to win it, and the French club, fourth from bottom of Ligue 1, withstood a spell of late pressure to record a famous victory and put themselves in command of Group B.
For Arteta and Arsenal, a first defeat of the season was the worst possible preparation for Sunday's crunch visit of Manchester City, and they will now face an anxious wait to discover the extent of Saka's injury.
The England winger, who made Jesus' goal, had been struggling for a couple of minutes before going down and receiving treatment, and he walked straight down the tunnel after being replaced by Fabio Vieira.
It is the third time in nine days that Saka has been forced off, following knocks in the League games against Tottenham and Bournemouth, and if it was a risk to play him, it backfired badly.
Saka has often appeared invincible, with Arteta encouraging him to take the next step towards superstardom by being decisive in matches three times a week.
There will, however, be legitimate questions about Arteta's handling of the 22-year-old if he has suffered a serious injury or simply cannot recover in time for this weekend's six-pointer. How much football is too much? The schedule is punishing on every elite player, particularly one who covers as much ground and takes as many kicks as Saka.
Admittedly, an impressive Lens side justified Arteta's decision to name a strong XI as they offered Arsenal a considerably sterner test than the 4-0 stroll past PSV Eindhoven at the Emirates, on the Gunners' return to the Champions League after a six-year absence.
Lens were themselves hosting a Champions League game after a far longer wait, for the first time in 21 years, and the Stade Bollaert-Delelis was rocking.
The Ligue 1 strugglers demonstrated their quality with the equalising goal, a cool first-time finish from Thomasson after David Raya lost possession with a poor kick towards right-back Takehiro Tomiyasu.
It was a redemption for Thomasson, who had carelessly passed straight to Saka for the opening goal on 14 minutes, Jesus collecting the winger's pass, dropping a shoulder and arrowing a superb effort into the far bottom corner.
But they were disjointed and flat on the night, and defeat was a reminder that you will be punished for being below par at this level.
That will also be true against City on Sunday and Arsenal's hopes of finally beating the champions may now depend on Saka's fitness.