Tom Rogers and Ben Carter both start at the Principality Stadium, while Gareth Thomas, Taine Basham and Ben Thomas are all set for their international debuts from the replacements.
Meanwhile, Halfpenny will win his 96th Wales cap, taking the full-back to a century when including his British & Irish Lions Test appearances.
Halfpenny combines with Scarlets teammate Rogers and Jonah Holmes in the back-three, while captain Jonathan Davies joins Uilisi Halaholo in a familiar centre partnership. Tomos Williams and Callum Sheedy link-up at half-back.
In the pack there is plenty of experience with Nicky Smith, Elliot Dee and Dillon Lewis bringing a combined 104 caps to the front-row.
Will Rowlands partners debutant Carter in an all-Dragons second-row, while Ross Moriarty, James Botham and Aaron Wainwright combine in the back-row.
“We are all looking forward to getting back to the Principality Stadium with fans in attendance and Saturday against Canada promises to be a great occasion,” said Wales head coach Wayne Pivac.
“This summer is an important block as we build towards Rugby World Cup 2023, and it is great to give five uncapped players opportunities.
“They have all impressed us in training, deserve a chance and we are looking forward to seeing them step up to the Test arena.
“At the other end of the scale you have Leigh Halfpenny, who makes his 100th Test appearance. It is a thoroughly deserved milestone for Leigh and it is made all the sweeter by the fact that his family and so many of our supporters are able to be in attendance.”
Ryan Elias, Leon Brown, Josh Turnbull, Kieran Hardy and Nick Tompkins join the debutants among the replacements.
Tickets for Wales v Canada can be purchased here.
WALES TEAM TO FACE CANADA ON SATURDAY, JULY 3 (15.00)
15 Leigh Halfpenny (Scarlets) (95 caps)
14 Jonah Holmes (Dragons) (5 caps)
13 Uilisi Halaholo (Cardiff Rugby) (4 caps)
12 Jonathan Davies (Scarlets) (88 caps)
11 Tom Rogers (Scarlets) (Uncapped)
10 Callum Sheedy (Bristol Bears) (9 caps)
9 Tomos Williams (Cardiff Rugby) (22 caps)
1 Nicky Smith (Ospreys) (39 caps)
2 Elliot Dee (Dragons) (37 caps)
3 Dillon Lewis (Cardiff Rugby) (28 caps)
4 Ben Carter (Dragons) (Uncapped)
5 Will Rowlands (Dragons) (7 caps)
6 Ross Moriarty (Dragons) (45 caps)
7 James Botham (Cardiff Rugby) (6 caps)
8 Aaron Wainwright (Dragons) (29 caps)
Replacements
16 Ryan Elias (Scarlets) (17 caps)
17 Gareth Thomas (Ospreys) (Uncapped)
18 Leon Brown (Dragons) (17 caps)
19 Josh Turnbull (Cardiff Rugby) (10 caps)
20 Taine Basham (Dragons) (Uncapped)
21 Kieran Hardy (Scarlets) (4 caps)
22 Ben Thomas (Cardiff Rugby) (Uncapped)
23 Nick Tompkins (Saracens) (10 caps)
