Scrum-half Murphy has been kept out of the side this season by England hopefuls Scott Bemand and Harry Ellis, while Humphreys has had to be patient with Andy Goode and Paul Burke sharing fly-half duties so far.
Goode has been named on the England bench for the Twickenham date with South Africa this weekend, while Burke took a knock which led to his withdrawal during the second half at Saracens last Sunday.
"Frank and Ian have played together all year in the second team and we want to retain that continuity and also provide them with the best possible environment to perform," said Tigers head coach Pat Howard. "Ian's other opportunities at this level have been away games and this is an opportunity for him to take second-team form into a first-team game."
With Dan Hipkiss withdrawing from the team to face Saracens last Sunday due to injury, Howard called in Leon Lloyd, and this week both are set to play, with Lloyd moving to the wing in his 250th appearance for Leicester and Hipkiss back in the No.13 shirt alongside Daryl Gibson in the midfield.
In the forwards, hooker Gavin Hickie starts his first game since his summer switch from Worcester Warriors.
"Gav performed well off the bench in the EDF Energy Cup and I want to keep the competition as tough as possible for places so he gets his chance," added Howard.
James Hamilton, who won his first senior cap for Scotland in the win over Romania last weekend, is named on the bench after returning to club duties in midweek.
Team
15 Sam Vesty
14 Leon Lloyd
13 Dan Hipkiss
12 Daryl Gibson
11 Tom Varndell
10 Ian Humphreys
9 Frank Murphy
1 Alex Moreno
2 Gavin Hickie
3 Michael Holford
4 Leo Cullen (capt)
5 Louis Deacon
6 Brett Deacon
7 Shane Jennings
8 Jordan Crane
Replacements
16 James Buckland
17 David Young
18 James Hamilton
19 Luke Abraham
20 Harry Ellis
21 Matt Cornwell
22 Johne Murphy
