The prolific off-spinner, five wickets away from surpassing retired Australian Shane Warne's world mark of 708, has ensured that Sri Lanka are a formidable, almost unbeatable, squad in their own backyard.
The hosts have won 15 of the last 25 Tests on their spin-friendly pitches, nine of them by big innings margins, and lost just four matches.
Observers say Sri Lanka's home advantage is just as real against England who, in the words of noted cricket writer Peter Roebuck, "find Murali harder to read than a Bulgarian novel."
Vaughan however can seek inspiration from his predecessor Nasser Hussain, who led England to a 2-1 win in 2001, one of only three Test series out of 19 in the last decade that Sri Lanka have lost at home.
Vaughan, on his third Test tour here, knows that his team will face a monumental task when the first Test starts at the Asgiriya stadium here.
"It is always difficult to win in this part of the world," the England captain said after his side recorded a morale-boosting win in a first-class match in Colombo on Tuesday.
He said he hoped England could put up big totals, despite the threat from Muralitharan, to give the bowlers a chance to win matches.
"You need to be able to defend more out here, and you need your areas to score," he said.
"Sri Lanka's attack is very experienced and disciplined, so there will be times when it's difficult to score, but I'm sure there will be times we can get on top of them."
After two practice matches in Colombo, Vaughan was still not sure whether Ravi Bopara or Owais Shah would take the number six slot left vacant by the injured Andrew Flintoff.
"The final eleven was always going to be a tough one, and that number six position is going to be especially tough whichever way we go," he said.
Strike bowler Steve Harmison is set to miss the first Test due to a niggling back injury, leaving Matthew Hoggard, Ryan Sidebottom and, possibly, James Anderson to share the new ball in the heavy conditions in Kandy.
Sri Lanka, meanwhile, hope to get back to winning ways after being blanked 2-0 in Australia earlier this month, but have their own problems trying to finalise the line-up.
Left-hander Upul Tharanga, who scored 112 and 86 against the tourists in the practice games, returns to the side after missing the Australian series and will open the batting with either veteran Sanath Jayasuriya or Michael Vandort.
Jayasuriya, 38, has scored just one half-century in his last 15 Tests and local media speculated he was being nudged by the selectors to announce his retirement during the series, or face the axe.
Veteran left-arm seamer Chaminda Vaas, dropped for the second Test in Australia, is back to play his 100th Test match as the pace spearhead alongside Lasith Malinga and Dilhara Fernando.
Muralitharan, however, promises to hog the spotlight as he bids to become Test cricket's most successful bowler in front of adoring fans in his hometown where he first learned the sport.
The 35-year-old may have claimed just four wickets in Australia this month, but he is expected to grab a rich haul on Sri Lankan pitches, where his last 25 Tests have fetched him an incredible 205 wickets.
Two bomb blasts rocked the capital Colombo on Wednesday, killing at least 18 people, but England team officials said the tour would go on as planned.