Saints must beat their Pool D rivals to keep alive any realistic chance of reaching the Millennium Stadium semi-finals next March.
And head coach Grayson has not minced his words in training this week following the dismal 24-12 home loss against Guinness Premiership strugglers Worcester last time out.
"Last weekend was the most hurtful weekend of my career as a coach so far because, going into the game, there was nothing but positives," he said.
"There were positive chances for people to claim a spot in the team, to show their worth and to show how much it means to them to play at home and for the fans.
"In group terms, losing to Worcester has put us on the back foot, no doubt about it.
"But we have no right to look at the group and at other scores after a performance like that. We were out-thought by an uncomplicated team, and that should not happen."
Although Saints' England wing Ben Cohen misses the trip to Wales because of a rib injury, Grayson recalls fit-again trio Carlos Spencer, Tom Smith and Pat Barnard, while flanker Ben Lewitt makes his first start of the season.
Worcester host fellow unbeaten challengers Leicester at Sixways on Saturday, knowing a first home win of the season would put them in pole position for the semi-finals, with only four pool winners progressing.
"If we win on Saturday and then we win the next three matches, we've won the competition, so we might as well carry on and do our best," said Worcester rugby director John Brain.
"But any director of rugby who tells you the Premiership is not the priority is being economical with the truth."
Ospreys head coach Lyn Jones has named a surprising line-up for Saturday's Pool A appointment with Bath at the Recreation Ground.
An emphatic victory over Gloucester a week ago installed the Ospreys as group favourites, although Bristol - who visit Kingsholm on Saturday - remain firmly in contention.
But Jones has caused confusion by announcing a side that does not include Gavin Henson, Justin Marshall, Shane Williams, Sonny Parker, Duncan Jones, Brent Cockbain or Ryan Jones.
"This week's preparations have been hugely disrupted due to Wales squad training commitments," Jones explained.
"As a result, we have brought in a lot of new players, but we have a strong squad and we are confident the players we've drafted in are more than capable of performing at this level."
It remains to be seen which Ospreys team actually takes the field, and Bath are not likely to take the current selection at face value.
Newcastle will be eliminated from Anglo-Welsh contention unless victory can be achieved against Kingston Park visitors Llanelli Scarlets on Friday night.
While the Falcons came unstuck 28-5 in their opening Pool C appointment with Sale Sharks, Llanelli brushed aside Premiership strugglers Harlequins to take top spot.
Newcastle welcome back fly-half Toby Flood, who suffered an injury during England training at Loughborough University last week, but full-back Matt Burke misses out due to a slight thigh problem.
The Scarlets have put Wales fly-half Stephen Jones on replacement duty, handing Ceiron Thomas their number 10 shirt, while wing Mark Jones returns instead of Darren Daniel, with props Phil John and Deacon Manu also gaining starts.
"We have built up a momentum over the past few weeks, which is very pleasing," said Scarlets rugby director Phil Davies, whose team are seeking a sixth successive win in all competitions.
"We are taking this competition seriously and have picked a strong squad. We feel we have got a pretty effective game-plan."
Quins host Sale on Saturday, with England centre Stuart Abbott back in action after serving a three-week ban and World Cup winner Andy Gomarsall making his full debut.