Davis played football for Syracuse University, and went on to national fame for three seasons (1959–1961), twice winning first-team All-American honors. As a sophomore in 1959, Davis led Syracuse to the NCAA Division I-A national football championship, capping an undefeated season with a 23-14 win over the University of Texas in the 1960 Cotton Bowl Classic, where Davis was named Most Valuable Player. That same season, Elmira Star-Gazettesports writer Al Mallette coined the nickname for Davis, the "Elmira Express". In his junior year, 1960, he set a record of 7.8 yards per carry and was the third leading rusher in the country with 877 yards, having rushed for 100 yards in 6 of 9 games. The 1960 Syracuse Orangemen finished with a record of seven wins and two losses and did not play in a post-season bowl game. In 1961, Ernie's senior year, the Orangemen finished with a record of 8 wins and 3 losses, closing with a 15-14 victory over the Miami Hurricanes in the Liberty Bowl, played at Philadelphia's Franklin Field. It is important to note that college football was using limited substitution rules at the time and players played both offense and defense.
Davis found discrimination prevalent in the American South during his Cotton Bowl Classic visit to host city Dallas, Texas. Author Jocelyn Selim writes that at the banquet following the 1960 game, Davis was told he could only accept his award and then would be required to leave the segregated facility. Davis and his black teammates were allowed to finish their meals at the banquet. When dessert was brought, a gentleman quietly approached them and told them they would have to leave when the doors were opened to the public for a dance. The three got up to leave and when the teammates found out, they wanted to leave too, but were told that it would only cause a bigger problem, so they stayed.
A different account of the banquet is given by John Brown. He was Davis' teammate at Syracuse and on the Cleveland Browns, his roommate and a close friend. According to an article in the Houston Chronicle, all the players from the game attended the banquet. Brown recalls that the teams sat on opposite sides of the room. After everyone ate and the trophies were handed out, the three black Syracuse players, including Brown and Davis were asked to leave and were taken to another party in Dallas by local NAACP representatives. One Syracuse player, Ger Schwedes, recommended that the whole Syracuse team leave the banquet to show solidarity with their black teammates, but the suggestion was overruled by Syracuse officials. When the Chronicle asked Brown whether the film is a truthful portrayal of his friend, Brown said " ... in short, no."
Davis became the first black athlete to be awarded the Heisman Trophy (the highest individual honor in collegiate football), following his 1961 senior-year season at Syracuse University. President John F. Kennedy had followed Davis' career and requested to meet him while he was in New York to receive the trophy. Later in 1963, when Elmira chose February 3 to celebrate Davis' achievements, Kennedy sent a telegram, reading:
Seldom has an athlete been more deserving of such a tribute. Your high standards of performance on the field and off the field, reflect the finest qualities of competition, sportsmanship and citizenship. The nation has bestowed upon you its highest awards for your athletic achievements. It's a privilege for me to address you tonight as an outstanding American, and as a worthy example of our youth. I salute you.
During his time at Syracuse, Davis wore the same number, 44, as legendary OrangemanJim Brown, helping to establish a tradition at the school that was acknowledged on November 12, 2005, when the school retired the number in an on-field ceremony. Davis also played basketball at Syracuse for one season 1960-1961. Syracuse University, as a way to honor all of the athletes that have worn the number 44, was granted permission by the United States Postal Service to change its zip code to 13244.
While attending Syracuse, Davis was a member of the Sigma Alpha Mu Fraternity, a nationally recognized Jewish fraternity. Davis was the first African-American to become part of the organization not only at the Syracuse chapter, but for the national fraternity as a whole.
The decision of the Redskins to draft Davis was a reluctant one by Redskins' owner George Preston Marshall. Marshall for years had refused to sign any black players, and the Redskins were the last NFL team to do so. He was a notorious racist, and backed his decision by stating that he wanted to appeal to the NFL's southern market. The signing only came when Interior SecretaryStewart Udall issued an ultimatum to Marshall: sign a black player, or the Redskins' 30-year lease on the D.C. Stadium (now the Robert F. Kennedy Memorial Stadium) would be revoked. The stadium was property of the Washington city government. Marshall's response was to draft Davis. Davis refused to play for the Redskins, and demanded a trade. In turn a trade to Cleveland was engineered by Browns Coach Paul Brown shortly after Art Modell had purchased the team and without the knowledge or consent of Modell. This was standard operating procedure with the Browns from their inception in 1946, as Brown was the General Manager and Head Coach.  Davis chose to go to the Cleveland Brown where his classmate John Brown would be his roommate and Jim Brown, whom he admired was already playing.
Davis signed a three-year, $200,000 contract with the Browns in late December 1961, again without the knowledge or consent of Modell, while he (Davis) was in San Francisco, California practicing for the East-West Shrine Game. Originally reported at $80,000, the contract, according to Davis' attorney, A. William (Tony) DeFilippo, consisted of $80,000 for playing football, including a $15,000 signing bonus; $60,000 for ancillary rights, such as image marketing; and $60,000 for off-season employment. It was the most lucrative contract for an NFL rookie up to that time. However, the Browns' dream of pairing Davis with Jim Brown in the backfield took a tragic turn when Davis was diagnosed with leukemia during preparations for the 1962 College All-Star Game and also at Browns training camp. The rift between Coach Brown and Modell worsened when Modell brought in doctors who said Davis could play pro ball but Brown refused to suit him up. This contributed to Modell's decision to replace Brown before the 1963 season. Ernie was allowed to practice on the field (without physical contact) and helped Brown with play plans for the team, but was never played. Brown was concerned that Ernie's condition, although in a remission brought the morale of the team down.
Davis never played a game as a professional, with his only appearance at Cleveland Stadium coming during a 1962 pre-season game, in which he ran onto the field as a spotlight followed him. Following his death, the Browns retired his number 45 jersey.
In the summer of 1962, Davis was diagnosed with acute monocytic leukemia and began receiving medical treatment. The disease was incurable and he died in Cleveland Lakeside Hospital May 18, 1963, at the age of 23. Ernie went to Johns Hopkins when he was dying, three months after being diagnosed and through chemical treatments experienced a 4-5 month remission. That was the time that the controversy between Paul Brown and Art Modell took place. Both the House and the Senate of the United States Congress eulogized Davis, and a wake was held at The Neighborhood House in Elmira, New York, where more than 10,000 mourners paid their respects. During the funeral, a message was received from President Kennedy, and was read aloud to all of the people attending the service. Davis is buried at Woodlawn Cemetery, Elmira, Chemung County, New York, in the same cemetery in which Mark Twain is buried. His commemorative statue stands in front of Ernie Davis Middle School, which Davis attended as Elmira Free Academy during his high school years. The building was named in his honor after its conversion to a middle school. Another statue of Davis stands on the campus of Syracuse University, near the steps of Hendricks Chapel and the Quad where pre-game pep rallies are held. He was elected to the college football hall of fame in the Fall of 2008, coinciding with the premiere of The Express and the beginning of construction of Ernie Davis Hall, a dorm on the Syracuse campus.