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.