The off-spinner's haul of six for 82 was the only thing that stood between England and a mammoth first innings lead on the second day of the second Test.
As it was, thanks to Kevin Pietersen's astonishing 142, England achieved a first innings lead of 154 and, by stumps, were looking at going 1-0 up in the three-match series after reducing Sri Lanka to 86 for four in their second innings - still 68 behind.
Muralitharan's return took his tally of Test wickets to 620 - a figure bettered only in the history of the game by Australia leg-spinner Shane Warne's total of 685.
It was also the 52nd time in 105 Tests that the 34-year-old Muralitharan, whose career has been dogged by controversy over the legitimacy of his extraordinary action, had taken five or more wickets in an innings.
But Murali, who has played county cricket alongside current England captain Andrew Flintoff at Lancashire, said his latest 'five for' mattered as much as his first.
"This one means a lot to me because I set a target when we were coming to England, that at least I would take five, six or seven wickets in a (Test) match because it's going to maybe be my last tour of England," he said.
"We will next be here in 2010. I don't know if I'll still be playing then.
"It's a very important tour for me, this tour so before I retire I want to do well again in England.
"From the team point of view, I'm a little bit disappointed but my personal performance today was good."
Few sides relish the prospect of a fourth innings on a wearing pitch against Muralitharan.
But, having seen his team bat for some 14 hours after being made to follow-on to save the drawn first Test at Lord's, the master spinner said the last six wickets needed to build a lead of 150 to give him a chance of spinning Sri Lanka to what would be an astonishing victory.
"I think we played poorly but we've still got six wickets in hand so we can fight but it's not easy.
"The minimum (lead) is 150 runs. If it's only a hundred or 80 runs, sometimes you take early wickets and it might become close but the opposition will still get it."
Muralitharan paid generous tribute to Pietersen, whose dashing 157-ball innings featured 20 fours and three sixes, one a remarkable reverse-sweep six against the off-spinner.
"He played a brilliant innings. It was one of the best I have seen."
And while he could recall being reverse-swept by former South Africa batsman Jonty Rhodes in a One-day International, Murali said of Pietersen's flamboyant stroke: "Nobody has hit a six before."
He added: "I think Pietersen is on top of the world at the moment, the way he is batting. He has got everything right in his armoury.
"His natural talent is to be aggressive and his record is unbelievable," added Murali of Pietersen, who has now scored 1,190 runs in 13 Tests at a high average of 51.74 with four hundreds.
The 25-year-old South Africa-born Hampshire batsman, who equalled his Test-best 158 at Lord's made the same score while facing county captain Warne in England's Ashes clinching draw at The Oval in September.
"They are both great bowlers," said Pietersen of the spin legends. "Over 600 wickets each. They are just amazing to watch and to bat against.
"I'm still new in the game, so it's fantastic to know that I'm facing these guys and doing OK."