The 2021 season was a year of growth for the Case Western Reserve University football team. Despite a roster that consisted mostly of first-years and sophomores who had never played in a collegiate game before, the Spartans matured into a formidable squad by the end of the season, completing the year with a 6-4 overall record and a 5-4 mark in Presidents' Athletic Conference play.

The 6-4 record for the Spartans marked the team's sixth-consecutive winning campaign. The team's 5-4 record conference play was good for a fifth-place finish in the PAC.

CWRU's trademark during the campaign was its high-powered passing offense, led by senior quarterback Drew Saxton, which finished the year ranked 13^th in Division III and led the PAC with 307.0 yards per game. The Spartans averaged 421.4 yards of offense overall in 2021, the 47^th-best mark in Division III and second-most in the PAC, while scoring 32.5 points per game, the 56^th-most in Division III and second in the PAC. Defensively, the Spartans allowed 26.1 points per game on 373.9 yards per contest.

Saxton, an All-PAC First Team selection for the third time in his career, finished the year 17^th among Division III quarterbacks with 3,029 passing yards, the fourth-highest total in program history. He also led all PAC quarterbacks with 23 passing touchdowns and was second in the conference with a 61.3% completion rate. Saxton's top targets during the season included junior wide receiver Lucas DeCaro, who had a breakout year with 52 catches for 814 yards and 10 touchdowns (all team-leading totals), senior wide receiver Colt Morgan (44 catches, 568 yards, two TDs), first-year wide receiver Ethan Dahlem (31 catches, 314 yards) and junior wide receiver Aidan Cain (29 catches, 289 yards, four TDs).  Junior running back Antonio Orsini paced the rushing game with 675 yards and 13 touchdowns, while adding 26 catches for 266 yards and another score, and senior Donald Day III added 238 rushing yards and a touchdown.

Junior defensive back D.J. Wolf led the defense with 68 total tackles and two interceptions, and sophomore linebacker Sean Torres added 67 tackles, including 4.5 for a loss. Sophomore defensive lineman Kaden Tong keyed the pass rush with a team-high 7.0 sacks and 11.5 total tackles for a loss. Other key contributors on defense for the Spartans in 2021 included senior linebacker Michael Amadio (51 tackles), senior defensive back Colin Schuster (37 tackles, eight pass breakups), sophomore linebacker Ryan Cabrera (49 tackles, 5.5 for a loss) and first-year linebacker Nate Cikalo (47 tackles, 5.5 tackles for a loss).

The Spartans opened the 2021 season with back-to-back wins on the road, defeating Rochester 27-20 in the team's only non-conference game of the season, before a dominating 66-33 win at Waynesburg in their conference opener. The 66 points scored in the game by the Spartans' offense against Waynesburg marked the second-most ever in program history, behind only a 70-point effort against Oberlin in 1998. CWRU also matched a team record with 28 points in the second quarter of the game, while Spartans' 575 yards of offense were the most by CWRU since 2017. Saxton earned PAC and UAA Athlete of the Week honors after throwing for career highs with 433 yards and five touchdowns.

Despite the team's early success, the Spartans' inexperience caught up with them by the third game of the campaign. CWRU suffered three-straight losses heading into the bye week, dropping 34-12 and 37-14 decisions at home to Westminster and 11^th-ranked Washington & Jefferson, and suffering a 42-40 road loss to Saint Vincent. In the loss to Saint Vincent, Saxton set school single-game records for completions (40) and attempts (65), while surpassing his career-best mark for yardage (462) once again, the second-highest single-game passing total in program history. Also in the Saint Vincent game, Morgan matched a school record with 15 receptions, while totaling 195 receiving yards.

The Spartans regrouped after their bye week, winning four-straight games. CWRU began the second half of their schedule with a resounding 53-0 win over Bethany at home, which marked the first shutout for the team since the 2017 NCAA Playoffs. The CWRU defense held the Bison to just nine rushing yards and 192 total yards in the game, both season-best marks. The following week, Saxton capped off a 46-second, 91-yard drive with a nine-yard touchdown pass to DeCaro with 20 seconds left on the clock to give the Spartans a thrilling 42-38 win over Geneva on Homecoming Day.

A 30-12 win at Thiel the following week assured the Spartans no worse than a .500 record heading into their final home game of the year against Grove City, one of the better teams in the PAC. CWRU saved one of its best efforts of the year for the Grove City contest, as the Spartans jumped out to a 20-0 lead by halftime, en route to a 35-21 win over the Wolverines.

CWRU ended its season with the 35^th-Annual Academic Bowl, falling to Carnegie Mellon 24-6 on the road.

During the 2021 campaign, Morgan set a new program record with 219 career receptions and increased his own , while finishing his time as a Spartan ranked third in program history with 2,899 yards. Saxton became just the second player in program history to eclipse 9,000-career passing yards and ended his senior campaign with a total of 9,028 yards. Saxton also moved into second place in program history with 83 career passing touchdowns.

In addition to the team's success on the field, 36 members of the Case Western Reserve football team received UAA Fall All-Academic Honors, presented to members of the team with a 3.3 cumulative grade point average, who have completed one full year of collegiate study. Three members of the team – Cain, graduate student Donny Genetin Jr., and senior Johnny Kass – were inducted into the Van Horn Society, an honor bestowed on students who have reached at least junior standing at the University and have a 3.8 or higher cumulative GPA.

The Spartans earned the following awards during the 2021 season:

The following were the Spartans' team statistical leaders during the 2021 season: