A chaotic, error-strewn performance from the Johannesburg side saw them fall to their fourth consecutive URC loss, a streak compounded by their recent elimination from the Challenge Cup.
With just three regular season fixtures remaining - all at home - the Lions sit 14th on the table with 31 points, having earned a bonus point for scoring three tries. It is now confirmed they will miss out on a top-eight finish for the fourth year running.
The Italian visitors came out firing, racing to a 22-3 lead within the opening 23 minutes thanks to three early tries.
Despite a brief fightback from the hosts, including tries from Ruan Venter and Marius Louw, Benetton maintained their dominance to lead 32-17 at half-time.
Benetton pulled further ahead early in the second half, extending the score to 39-17 before the Lions found late consolation through Edwill van der Merwe in the 61st minute and JC Pretorius in the 77th. A penalty by Jacob Umaga added gloss to the visitors' tally.
The Lions' performance was plagued by poor handling, ill-discipline, and questionable decision-making - hallmarks of a team unable to match the tempo and execution required at this level.
Springbok forward Ruan Venter returns to the Lions starting XV as one of two changes made by coach Ivan van Rooyen ahead of their United Rugby Championship clash with Scarlets at Ellis Park on Sunday.
Sharks coach John Plumtree is without five of his Springboks for their United Rugby Championship match against Ospreys on Friday.
Springbok behemoth Eben Etzebeth will captain the Sharks in their Round 17 United Rugby Championship clash with Ospreys at Hollywoodbets Kings Park on Friday night.
The Bulls have a chance to move up into second place on the United Rugby Championship table with a win over Cardiff this weekend.
