It was almost three straight from kick-off as Duran fired into the side netting, but Celtic failed to heed that warning as Prestianni played Duran through minutes later and the Colombian striker beat Sinisalo from a tight angle.
It was alarmingly easy for a classy Benfica outfit to cut through Celtic, as reflected by their 26 shots at goal - 21 of those coming in the opposition box.
O'Neill withdrew club-record signing Kasper Hogh - who has now failed to score in 10 of his first 11 Celtic appearances - and Tounekti at half-time as he searched for a much-needed spark.
The introduction of Haissem Hassan and Osmand had the desired effect. Hassan shot straight at Trubin and teed up Duran's goal, but Benfica continued to create chances seemingly at will.
Andreas Schjelderup rattled the post and Pavlidis added the fourth goal the hosts' play deserved late on.
Admittedly, this was not a game Celtic were expected to win, but they failed to even compete for long periods and were their own worst enemy at times with unforced errors.
They host Hearts in the league on Sunday in a big test before returning to European action against Celta Vigo.