Stanford (1-0) returns to action from a one-week layoff after opening the season Aug. 26 in Sydney, Australia, with a rout of Rice. The Cardinal seeks to win a fourth straight against the Trojans (1-0) and to reassert its place in the conference championship race.
This marquee matchup falls in September for a fourth straight season and for the fifth time in six years. Such a high-profile date this early provides an interesting measuring stick for the remainder of the season.
"I enjoy it," Stanford defensive lineman Harrison Phillips said of drawing the Trojans early into the campaign. "It's very important to have a test that early in the season that proves every suspicion and proves our ambitions of what can come true."
Phillips noted winning or losing this one doesn't mean everything, though. He cited USC rallying from a 27-10 loss to Stanford last September to reach the Rose Bowl, while the Cardinal finished 6-3 in Pac-12 play.
Nevertheless, this matchup has taken on a rivalry feel.
"It's one of those dates you mark on your calendar, because you know it's going to impact your season," USC head coach Clay Helton said.
"(Stanford head coach) David (Shaw) has done a tremendous job there ... building that program to what it is today. The consistency that he brings to the table with his program, year in and year out, is very impressive."
That consistency is evident in three conference championships from 2012 to 2015. Last year marked Stanford's sixth season with 10-plus victories since 2010.
The run games, as they have in the past, figure to take center stage.
USC junior Ronald Jones II went for 159 yards and three touchdowns on just 18 carries in a 49-31 victory against Western Michigan.
"He reminds you of (former NFL All-Pro) Jamaal Charles," Shaw said. "More physical than people will give him credit for, he'll run through tackles. He's gotten bigger since last year. He's explosive, catches the ball out of the backfield; just a dangerous football player."
USC adds another element of danger to its ground attack with freshman Stephen Carr. Carr made a splash in his collegiate debut, rushing for a pair of touchdowns.
The Cardinal counters with its own two-man look.
Stanford's Bryce Love, taking over for All-American Christian McCaffrey, rushed for 180 yards. Cameron Scarlett rushed just eight times against Rice, but scored three touchdowns.
Further underscoring the importance of the run game: In nine of 10 meetings since 2008 -- and each of the last four -- the team with the rushing advantage won. USC seeks a dramatic improvement from its Week 1 performance, when it surrendered 263 yards to Western Michigan -- the most the Trojans allowed since Stanford went for 302 last September.
Run-stoppers will play central roles in Saturday's affair, and both Stanford and USC feature some of the Pac-12's best. The Trojans will have preseason All-American inside linebacker Cameron Smith available for a full 60 minutes for the first time on the season.
Smith missed the first half of last week's game while serving a one-half suspension due to a targeting penalty in the Rose Bowl. USC's performance against the run improved upon his return.
Few teams in the Pac-12 can match USC's experience in the front seven, between Smith and Uchenna Nwosu at linebacker, with Porter Gustin and Rasheem Green on the line, but Stanford's such an exception. Phillips sets the tone up front, with upperclassmen Peter Kalambayi, Sean Barton, Joey Alferi and Bobby Okereke at linebacker.
USC-Stanford began to become competitive a decade ago. Shaw credits a Cardinal win in 2007 -- until this year, the largest upset in college football history -- for providing the launching point to Stanford becoming a nationally relevant program.
"I mark (2007) as the beginning of the program, where we started to be taken more seriously here at Stanford," Shaw said. "We hadn't arrived yet ... but the makings were there of a tough, physical football team that could go on the road and win a tough game."
Winning on the road has remained a theme for Stanford football in the past decade.
Dating to 2007, the Cardinal has won four of five games at the Coliseum. In contrast, USC's victory over Western Michigan marked the Trojans' 11th consecutive win at home.
USC is undefeated at the Coliseum since Helton took over as head coach midway through the 2015 season -- but also winless against Stanford at 0-2.