Alabama opened the season with a 110–0 victory over the Marion Military Institute which still stands as the school record for largest margin of victory and as the Crimson Tide's only 100 point game. After a victory over Oglethorpe, Alabama went winless over their next three games with losses at both Georgia Tech and Texas and a tie against Sewanee at Rickwood Field. With a record of 2–2–1, Alabama entered their intersectional contest against undefeated Penn as a major underdog. Alabama managed to upset the Quakers 9–7 in a game The Plain Dealer called "intersectional history". The Crimson Tide then completed their season with a homecoming win over LSU, a loss at Kentucky, a win over Georgia in Alabama's first game at the Cramton Bowl and a win over Mississippi A&M to close the season.
Scott coached the 1922 season while dying of oral cancer, and he spent the whole season suffering from the effects of his illness, losing weight, barely able to speak, coaching against the advice of a doctor who told him to quit immediately, and bedridden except when attending practices and games. After the Oglethorpe game Scott tendered his resignation, effective at the end of the season. Scott died in April 1924 at age 41.
To open the season, Alabama played the Marion Military Institute at Tuscaloosa, and defeated the Cadets 110–0 in what was the most lopsided victory in the history of the Crimson Tide football program. Against Marion, Alabama shutout the Cadets 55–0 at Tuscaloosa for their third consecutive win to open the season. Touchdowns were scored four times by Max Rosenfeld, twice by William C. Baty and once each by Al Clemens and Virgil Hawkins. The victory improved Alabama's all-time record against Marion to 8–0.
After their record setting victory over Marion to open the season, Alabama prepared for an Oglethorpe squad that nearly upset Georgia Tech in their opening game. In what was the first all-time meeting against the Petrels, Alabama won 41–0 before 3,000 fans at Tuscaloosa. In the game, Charles Bartlett starred for Alabama as he scored five of their six touchdowns in the victory. Bartlett scored touchdowns on a 26-yard run in the first, a 15-yard reception from Hulet Whitaker in the second, and on a pair of runs in the third and one in the fourth. Graham McClintock scored the final touchdown of the game with his short run in the fourth and made he score 41–0.
In what was their first road game of the season, Alabama was defeated by the Georgia TechYellow Jackets 33–7 at Atlanta. All of the scoring in the game occurred in the first half and the Yellow Jackets took a 33–0 lead en route to the win. Georgia Tech scored on first quarter runs of six-yards by J. J. McDonough and eight-yards by D. I. Barron; in the second quarter they scored on runs by Alexander Hunt and Barron. The Yellow Jackets then scored their final touchdown on a 20-yard McDonough pass to Hunt late in the second quarter. Alabama responded with their only points just prior to halftime when W. S. Oliver returned a McDonough kickoff 95-yards for a touchdown. The loss brought Alabama's all-time record against Georgia Tech to 2–7–1.
In the first Rickwood Field game of the season, Alabama tied the SewaneeTigers 7–7 for their lone tie of the season. After a scoreless first quarter, the Crimson Tide took a 7–0 lead after Charles Bartlett threw a 60-yard touchdown pass to Allen MacCartee in the second. Sewanee responded in the third when Bill Coughlan intercepted a Bartlett pass and returned it 70-yards and tied the game 7–7. Although they outplayed the Tigers throughout the game, Alabama was unable to win due to their numerous turnovers made throughout the contest. The tie brought Alabama's all-time record against Sewanee to 4–10–3.
In their second road game of the season, Alabama was defeated by the TexasLonghorns 19–10 at Clark Field in Austin. Alabama took an early 7–0 lead in the first two minutes of the game after Charles Bartlett threw a 25-yard touchdown pass to William Baty. Texas responded with a pair of touchdowns later in the quarter for a 13–7 lead. The first came on a Ivan Robertson pass to George Gardere and the second on a Yancy Culp run. A Robertson field goal in the second quarter extended the Longhorns lead to 16–7 at halftime.
After a 31-yard Robertson field goal in the third extended the Texas lead, Alabama scored the final points of the game on a short L. O. Wesley field goal later in the quarter and made the final score 19–10. The loss brought Alabama's all-time record against Texas to 0–3.
Alabama entered their intersectional contest against undefeated Penn, coached by John Heisman, with noted sports columnist Grantland Rice having predicted a 21–0 Quaker victory. Although the entered as an underdog, The Philadelphia Inquirer noted the Crimson Tide as a veteran squad that had not reached their full potential and expected them to plat Penn tough. Before 25,000 fans at Franklin Field, Alabama upset the Quakers 9–7 in what was later recognized as one of the Crimson Tide's most significant victories in the history of the program.
After a scoreless first quarter, Alabama took a 3–0 lead after L. O. Wesley connected on a 34-yard field goal. G. H. Sullivan responded later in the quarter with his 35-yard touchdown run that gave the Quakers a 7–3 halftime lead. In the third quarter the Crimson Tide took the lead after Pooley Hubertfumbled on third and goal and teammate Clyde Propst recovered the ball for a touchdown. The extra point failed, but Alabama took a 9–7 lead. Twice in the fourth quarter Alabama missed field goals, leaving Penn with a chance to win late. The Quakers drove to the Alabama 30 in the final moments but on fourth down Alabama came up with a sack to clinch a 9–7 victory.
On the Friday after their upset victory at Philadelphia, Alabama returned to Tuscaloosa and before the then largest crowd in the history of Denny Field on homecoming and defeated LSU 47–3. After a scoreless first quarter, Charles Bartlett scored on a ten-yard run for a 7–0 Crimson Tide lead. Allen Graham MacCartee then extended their lead to 13–0 with his short touchdown run, and the Tigers responded with their lone points of the game on a 28-yard Roland Kizer drop kick. Alabama then extended their lead to 27–3 at halftime behind a five-yard Hulet Whitaker run and short Bartlett pass to Al Clemens.
Early in the third, a Graham McClintock fumble gave LSU possession deep in Crimson Tide territory. On the play that ensued, Pooley Hubertintercepted a Kizer pass and returned it 65 yards for a touchdown. A five-yard Bartlett touchdown run later in the quarter extended the Alabama lead to 41–3 as they entered the fourth. Playing almost exclusively reserves in the final period, Bartlett made the final score 47–3 with his five-yard touchdown run. The victory brought Alabama's all-time record against LSU to 6–3–1.
In rain soaked conditions on a soggy field, Alabama was defeated 6–0 by Kentucky at Lexington. The Wildcats scored the only points of the game in the third quarter on a six-yard Bruce Fuller touchdown run. The loss brought Alabama's all-time record against Kentucky to 1–1.
Playing their first all-time game at the Cramton Bowl, the Crimson Tide overcame an early 6–0 deficit and defeated the GeorgiaBulldogs 10–6. The Bulldogs scored first after John Fletcher recovered a Allen Graham MacCartee fumble and returned it 96-yards for a touchdown.
Alabama responded with a short Charles Bartlett touchdown run in the second and with a 20-yard Bartlett field goal in the third for the 10–6 win. The victory improved Alabama's all-time record against Georgia to 5–9–3.