Erik ten Hag's side – denied a place in the final by Tottenham last season – was in dominant mood against their Ligue 1 opponent and looked well placed to claim all three points from the outset in Amsterdam.
Quincy Promes headed it into an 18th-minute lead before Edson Alvarez scored his first goal for the club five minutes after the interval.
Nicolas Tagliafico added a third with a thumping header after 62 minutes as the Dutch champions stormed into pole position in Group H.
Ajax started on the front foot and went agonisingly close to taking the lead in the 14th minute, Hakim Ziyech's thunderous half-volley crashing back off Mike Maignan's right-hand post.
It did not have to wait long to go ahead, though, as an unmarked Promes met Tagliafico's deep cross with a powerful header just four minutes later.
Lille responded well to that early setback and should have pulled level moments before the interval. Jonathan Bamba picked out Jonathan Ikone after a surging run down the left but Andre Onana got down well to keep out his low effort, with Victor Osimhen hooking the rebound over the crossbar.
The host looked sharp at the start of the second period, Ziyech testing Maignan low down to his left with a fierce drive.
The positive approach was rewarded in the 50th minute when David Neres slid Alvarez in down the right after a flowing team move and the Mexican superbly lifted a shot across the Lille goalkeeper from a tight angle to double their advantage.
Tagliafico ensured there would be no dramatic comeback from Lille when he made it 3-0 shortly after the hour mark, superbly heading home Ziyech's outswinging corner.
Yusuf Yazici crashed an effort against the post late on as Lille tried in vain to restore some respectability to a scoreline that did not flatter the hosts.