Michigan State vs. USC Picks and Prediction, Saturday, September 20, 2025

On Saturday, the Michigan State Spartans will face the USC Trojans at the Los Angeles Memorial Coliseum in Week 4 NCAAF action. Southern Cal is an 18-point spread favorite, and the game total is 55 points scored. Kickoff is scheduled for 8:00 p.m. PT.

This Michigan State vs. USC prediction highlights an undefeated Spartans team against a Trojans squad earning national buzz after three double-digit wins. This is the ninth meeting between these Big Ten opponents (series is tied 4-4). MSU won the most recent matchup 17-16 in the 1990 Sun Bowl.

Do you need a boost in your handicapping? Try our NCAAF Predictions.

Can Michigan State take the next step?

Michigan State (3-0 SU, 0-3 ATS, and 2-1 O/U) has kicked off the season with wins over Western Michigan (23-6), Boston College (42-40), and Youngstown State (41-24).

The Spartans held off a resilient Penguins team last week, as junior QB Aidan Chiles was 22-for-29 passing for 270 yards with 76 rushing yards. Michigan State led 31-10 in the third quarter, but Youngstown State kept the home team on its toes. MSU outgained YSU 444-339 in total yards, averaging 9.3 yards per pass and 5.3 yards per carry. It was a bit of a hangover performance following the Spartans' thrilling overtime victory over Boston College, but a win is a win nonetheless.

Chiles leads the MSU offense with 656 passing yards (71.6% CMP%), six touchdowns, and one interception. His development has been noticeable, a season after committing 15 turnovers, as his lone turnover was a fluke tipped pass intercepted by a defensive tackle. Chiles has also been more mobile, rushing for 123 yards in three games after rushing for only 225 yards in 2024. The California native has benefitted from an improved receiving corps, as Michigan State added transfer receiver Omari Kelly (15 receptions for 184 yards this year) to take pressure off leading receiver Nick Marsh (16 receptions for 194 yards and three TDs). The Spartans' ground game is also improved, with sophomores Makhi Frazier (43 carries for 206 yards and two TDs) and Brandon Tullis (18 carries for 112 yards and two TDs) sharing the load.

Michigan State scores 35.3 points per game (51st) and averages 386.7 total yards (73rd), including 218.7 passing yards (76th) and 168.0 rushing yards (67th). The Spartans' defense allows 23.3 points (76th) and 337.7 total yards (72nd) per game, including 273.3 passing yards (117th) and 64.3 rushing yards (17th).

Michigan State Spartans Football Injury Report:

L. Vincic OG Out - Undisclosed A. Brown WR Out - Undisclosed N. Marsh WR Questionable - Lower Body M. Frazier RB Questionable - Lower Body S. Chaney DL Questionable - Undisclosed A. Brinson IV CB Questionable - Undisclosed C. Luniewski OG Questionable - Foot C. Gash CB Questionable - Undisclosed T. Ahmetbasic K Questionable - Undisclosed A. Lepo OG Questionable - Undisclosed K. Schickel LS Questionable - Undisclosed J. Satchell DL Questionable - Undisclosed

USC is back in the top 25

USC (3-0 SU, 2-1 ATS, and 2-1 O/U) has taken down Missouri State (73-13), Georgia Southern (59-20), and Purdue (33-17) in its first three games.

The Trojans handled their business on the road in West Lafayette, forcing three interceptions on defense. Southern Cal outgained Purdue by over 100 total yards, averaging 10.1 yards per pass and 4.5 yards per carry to win the time of possession battle by over eight minutes. The Trojans were only 4-for-13 on third down but converted all four of their fourth-down attempts.

Junior QB Jayden Maiava has been impressive in his first season in Los Angeles. The UNLV transfer has completed 68 percent of his passes for 989 yards (14.1 YPA), six touchdowns, and zero picks. He ranks first nationally in QBR (94.3). USC has a wealth of talent at the receiver position, headlined by junior WRs Makai Lemon (16 receptions for 311 yards and two TDs) and Ja'Kobi Lane (nine receptions for 239 yards and one TD). The men from Troy also feature three running backs with at least 150 yards: junior Waymond Jordan (39 carries for 286 yards and three TDs), senior Eli Sanders (23 carries for 160 yards and two scores), and frosh King Miller (11 carries for 152 yards and two TDs).

USC scores 55.0 points per game (2nd) and averages 604.0 total yards (1st), including 364.0 passing yards (6th) and 240.0 rushing yards (19th). The Trojans' defense surrenders 16.7 points (43rd) and 319.3 total yards (59th) per game, including 233.0 passing yards (97th) and 86.3 rushing yards (21st).

USC Trojans Football Injury Report:

C. Johnson CB Out - Knee C. Chittenden K Out - Undisclosed P. Strachan WR Questionable - Undisclosed A. Graham CB Questionable - Undisclosed P. Brown CB Questionable - Undisclosed B. Jackson RB Questionable - Undisclosed

Michigan State vs. USC Pick

Spread Pick for Michigan State vs. USC

• USC -18 (4 Units)

Chiles has been excellent this season, but he could be without two key weapons in Frazier and Marsh, who are questionable. The Spartans' offensive line could also be in for a long night, as the Trojans rank second nationally in sacks and tackles for loss. MSU has struggled to keep opponents out of the backfield, and with two of his top playmakers unavailable or hampered, Chiles will have too much on his shoulders on Saturday.

I also expect Maiava to fare well, as Michigan State's secondary struggled to defend Boston College's passing game a couple of weeks ago (390 yards allowed). The Trojans' signal-caller will have no problem working the football down the field with short and intermediate passes until he can hit a few deep balls later in the game to really open things up.

Over/Under Pick for Michigan State vs. USC

• Under 55 (5 Units)

If MSU's top rusher and receiver are unable to suit up, I lean towards the under. There's no denying that the Spartans can put points on the board, but their depth would be tested without Frazier and Marsh. Extra pressure on Chiles could result in some of the turnover issues that plagued him last season, too. If the visitors are unable to keep up on offense, the Trojans will likely play more conservatively in the second half, eating up the game clock by running the football. USC has a challenging upcoming schedule (Illinois, Michigan, Notre Dame, and Nebraska), and won't risk injuries to its starters in a game that's already decided.