The two clubs have played out some hugely entertaining meetings during the past decade, though the results have rarely gone the way of the black, green and gold.
In fact, Saints have won just one of their six clashes with Clermont, with that lone victory coming at the Gardens back in January 2018.
Four of the six matches have been played away from home, at the hugely atmospheric Stade Marcel Michelin, including quarter-finals in the Champions Cup and Challenge Cup.
And now another knockout tie is on the agenda, this time in Northampton, as Phil Dowson's men bid to book their place in the last eight of the Champions Cup once again.
When the draw became clear, Saints boss Dowson reflected on his club's history with Clermont.
"I'm thinking of Teimana Harrison’s hat-trick out there recently (in 2019)," Dowson said.
"It's a great place to play, a huge European club, a great tie for the Saints in the round of 16 to play a club of that nature.
"They will be very well supported and it will be another classic in Europe."
Here's a look back at Saints' six European meetings with Clermont...
5. January 12, 2019: Clermont Auvergne 48 Saints 40
Phil Dowson was on Chris Boyd's coaching team when Teimana Harrison scored a hat-trick in a defeat at Clermont in the Challenge Cup pool stages in January 2019. Fraser Dingwall, Alex Mitchell and Cobus Reinach also scored in the match at Stade Marcel Michelin. Photo: Shaun Botterill
6. March 31, 2019: Clermont Auvergne 61 Saints 38
Taqele Naiyaravoro was yellow carded in the 28th minute and Saints conceded three tries during the first of the Challenge Cup quarter-final at Stade Marcel Michelin but they bounced back strongly before suffering defeat. Ahsee Tuala, Luther Burrell, Alex Mitchell, Rory Hutchinson and Alex Moon all scored during a hugely eventful second half. Photo: David Rogers