Murphy was used sparingly in his Ashes debut at Headingley, bowling just 9.4 overs for the match, including just two overs late in the second innings as England chased down 251 for victory.
It is an 11-year first for Australia, who hasn’t entered a test without a frontline spinner since facing India at the WACA in 2012.
Australian skipper Pat Cummins declared the decision not to be based on form, with conditions last week, as well as the forecast for the Manchester Test this week, better suited to pace bowling.
“We are really excited by Todd, we think he’s fantastic. I would have loved to use him a bit more last week, (but) conditions just favoured pace bowling,” he said.
“We played a Test in Hobart last year in the Ashes where Nath (Nathan Lyon) didn't bowl an over. It’s all conditions based.
“We are really excited by Todd, we think he’s a gun, we love having him around, he’s got a big future. It was more conditions the way I used him, as opposed to how he bowled.”
The off-spinner makes way for Cameron Green, with the all-rounder returning from a hamstring injury, while Mitchell Marsh retains his place in the side following his magnificent 118 in Headingley.
Scott Boland is the other Australian casualty, a straight swap for the returning Josh Hazlewood.
Tellingly, England has included Moeen Ali in its line-up, with the spinner boasting an impressive record at Old Trafford having claimed 16 wickets at an average of 18.5 across his three tests at the venue.
The Test commenced on Wednesday night, with English skipper Ben Stokes winning the toss and opting to bowl first.
Half centuries to Mitch Marsh and Marnus Labuschagne helped Australia build a competitive overnight score of 8-299, but 4-52 to Chris Woakes helped England prevent the Aussies from capitalising on a strong start.
Australia leads the series 2-1 after England’s victory in Leeds, and can secure the first Ashes series win in England since 2001 if it takes the win in Manchester, while only a draw is needed to retain the urn.
The fourth Ashes Test continues tonight, with play scheduled to resume at 8pm AEST.
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