The Ireland international made his debut for the club in 1997 and has subsequently won seven Premiership titles, two Heineken Cups and the LV= Cup.
"Reaching 300 games for the club is an excellent achievement and Geordan will go down in the list of Leicester Tigers all-time greats," said director of rugby Richard Cockerill.
"He is an outstanding player and captain, and he has shown great loyalty to Leicester over the years. I'm sure he'll receive a great reception from the supporters this weekend and he thoroughly deserves it."
With Manu Tuilagi and Toby Flood back involved with the England squad Scott Hamilton and George Ford come into the starting XV.
Hamilton starts on the wing with Matt Smith shuffling in to partner Billy Twelvetrees in the midfield - with Anthony Allen missing out.
The other changes come on the bench, with Julian White, Jeremy Staunton and Niall Morris called in.
Newcastle's trio of new signings will have to wait to make their debuts for the club.
Peter Stringer is not available until his deal with Saracens ends at the start of March, while James Goode and Adam Balding have not been included following their moves from Ospreys and Worcester respectively.
Boss Gary Gold has made two changes to his line-up, though, with Jeremy Manning and Andrew van der Heijden coming in.
Manning starts on the wing, while van der Heijden replaces the suspended Adriaan Fondse.
There is also a place on the bench for back-rower Richard Mayhew.
Leicester: 15 Geordan Murphy (capt), 14 Horacio Agulla, 13 Matt Smith, 12 Billy Twelvetrees, 11 Scott Hamilton, 10 George Ford, 9 James Grindal, 8 Thomas Waldrom, 7 Julian Salvi, 6 Steve Mafi, 5 George Skivington, 4 Ed Slater, 3 Logoviii Mulipola, 2 George Chuter, 1 Marcos Ayerza.
Replacements: 16 Rob Hawkins, 17 Boris Stankovich, 18 Julian White, 19 Graham Kitchener, 20 Craig Newby, 21 Scott Steele, 22 Jeremy Staunton, 23 Niall Morris.
Newcastle: 15 Greg Goosen, 14 Tom Bedford, 13 Jamie Helleur, 12 James Fitzpatrick, 11 Jeremy Manning, 10 Jimmy Gopperth (c), 9 Chris Pilgrim, 8 Mark Wilson, 7 Will Welch, 6 Ally Hogg, 5 Tim Swinson, 4 Andrew van der Heijden, 3 Euan Murray, 2 Rob Vickers, 1 Grant Shiells.
Replacements: 16 Michael Mayhew, 17 Jonny Golding, 18 Ashley Wells, 19 Taiasina Tu'ifua, 20 Richard Mayhew, 21 Will Chudley, 22 Rikki Sheriffe, 23 Joel Hodgson.
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