Erik ten Hag's entertainers took a solitary point from their back-to-back meetings with Chelsea but Hakim Ziyech put them ahead early on at the Stade Pierre-Mauroy.
A hero of last season's unlikely run to the semi-finals, Ziyech's brilliant goal launched an outing where the Eredivisie champion was typically dazzling and vulnerable.
Lille's finishing let them down, however, with Jonathan Bamba and Jonathan Ikone the main culprits, before Quincy Promes made sure of victory.
Ajax's opener came after 94 seconds and in delightful fashion.
Wonderful one-touch passes from Sergino Dest and Donny van de Beek ended with Zakaria Labyad picking out skipper Dusan Tadic, whose lay-off allowed Ziyech to dispatch an unerring strike past Mike Maignan.
The goalscorer returned the favour when Tadic had a powerful angled effort saved in the 12th minute, while Victor Osimhen's theatrical tumble inside the Ajax area underlined Lille's early desperation.
Bamba tracked back diligently to make a vital interception as a lurking Dest hoped to put Ajax 2-0 up, but the Lille winger had a moment to forget in the 31st minute when he blazed over from six yards with the goal at his mercy.
Lille resumed on the front foot, only for Ikone to join Bamba by producing a horror miss.
Osimhen muscled past Perr Schuurs after Lisandro Martinez's poor header and cut back for Ikone to lift inexplicably beyond the crossbar with the outside of his right boot.
Martinez stepped out of defence with a composure belying his early second-half efforts and found Ziyech on the right to curl a cross towards Promes for a smart back-post finish.
Lille stuck gamely to its task, although Andre Onana's superb double save from Bamba and Yusuf Yazici ensured its endeavours ended without reward.
Ziyech was denied a deserved second by a VAR handball verdict as Ajax kept pushing and Van de Beek thudded a powerful effort against the post.