Saints once again threatened a stirring second-half comeback at Stade Marcel Michelin - but Chris Boyd's men were eventually beaten 61-38 by Clermont Auvergne.
The black, green and gold had roared back after the break at the same ground in January, eventually being edged out in 48-40 in the Challenge Cup pool match.
And it was a similar if more comprehensive story on Sunday evening as Clermont eventually got over the line in style to book their place in the semi-finals.
Saints had been 37-10 down during the second period, but they roared back to just six points behind with 14 minutes remaining.
That only served to sting Clermont into life though as the Top 14 giants racked up a total of eight tries on the night.
Saints scored five of their own, with some sublime efforts among them, but they were outgunned by a formidable Clermont side who will fancy their chances of going all the way to glory in the Newcastle showpiece.
Saints were under pressure from the off as Damian Penaud did brilliantly to claim the Clermont kick-off and they quickly won a penalty, which Morgan Parra landed with ease.
But there was almost an immediate response from Saints as Dan Biggar gathered an overthrown lineout and charged towards the line before Clermont did brilliantly to hold Api Ratuniyarawa up in front of the posts to win a turnover.
Saints kept coming though and after some superb work down the left wing by Taqele Naiyaravoro, Cobus Reinach charged over the whitewash, only to be deemed to have been held up by some brilliant last-ditch defending from Peceli Yato.
It was a huge let-off for Clermont as Reinach had looked certain to score, but Saints did at least come away with three points after winning a penalty at the resulting scrum.
The men red and white were showing plenty of belief with ball in hand, but the dangers going in the opposite direction were obvious, with Alivereti Raka and Apisai Naqalevu proving particularly hard to stop.
And it was Naqalevu who opened the door for Clermont's first try, sending Peter Betham away down the left and, despite the best efforts of Teimana Harrison, the centre was able to dive over the line in dramatic fashion.
Parra missed the conversion from the touchline, but Saints were now rocking and Clermont had their tails up.
It was soon three scores for the home team as referee George Clancy handed them a penalty try after Naiyaravoro was yellow carded for a no-arms tackle on Arthur Iturria when the onrushing flanker was five metres from the line.
That put Saints 22-3 behind and with Clermont now rampant, there appeared to be no way back.
There was huge escape when James Fish failed to find his man from a lineout as hooker Benjamin Kayser knocked on with the line in sight.
The Saints lineout really wasn't functioning at all, giving Clermont possession time and again, leading to Fish being replaced by Reece Marshall before the break.
Saints desperately tried to summon a response, but George Furbank was flung into touch at the last from a promising position.
Clermont were 22-3 up at the break, and it was soon 25-3 after the restart as Parra landed another penalty.
Saints were dealt yet another blow when Courtney Lawes was forced off just six minutes into the second period.
And it wasn't long before Clermont had their fourth try of the game as they again shut Saints out before piecing together a quick break, which ended with Betham holding off Tom Collins and stretching out an arm to score.
Parra missed the conversion but his side were now well clear and Saints opted to empty their bench in a bid to freshen things up and with two key Premiership games coming up in the next two weeks.
And Ahsee Tuala made an immediate impact after coming on for Biggar, putting the finishing touches to a flowing Saints move.
Rory Hutchinson, now on kicking duties, converted, but Clermont were straight back at Saints after catching the kick-off, and Penaud scored.
Greig Laidlaw added the extras to make it 37-10, but Saints then threatened to mount a stunning comeback.
Luther Burrell produced a tidy finish after Saints had taken a quick tap penalty and then Alex Mitchell, who had just delivered a superb tackle on Yato, finished off another slick move.
Hutchinson added the extras on both occasions and Saints were starting to believe again.
That belief grew when Hutchinson scooted through a wide open Clermont defence to get the nerves jangling in the stands.
The centre kicked the conversion to bring Saints to just six points behind with 14 minutes remaining.
But that finally stung Clermont into life and after Laidlaw landed a scrum penalty, Raka's great work down the left gave them the territory to score through a neat finish from full-back Tim Nanai Williams.
Laidlaw kicked the conversion to make it 47-31 with seven minutes to go, extinguishing the Saints fightback.
And it was to get much worse as Penaud and Betham both scored again before Saints had the final say thanks to a Moon try and Hutchinson's conversion.
Clermont Auvergne: Nanai Williams (Grosso 76); Penaud, Betham, Naqalevu, Raka; Lopez, Parra (c) (Laidlaw 58); Falgoux (Kakabadze 73), Kayser (Ulugia 58), Slimani (Simutoga 58); Timani, Jedrasiak; Yato, Iturria (Lapandry 58), Lee.
Saints: Furbank; Collins, Hutchinson, Francis (Burrell 54), Naiyaravoro; Biggar (Tuala 54), Reinach (Mitchell 50); Waller (c) (van Wyk 50), Fish (Marshall 35), Hill (Franks 50); Moon, Ratuniyarawa; Lawes (Gibson 46), Ludlam (Brüssow 54), Harrison.
Referee: George Clancy (Ireland)