The 49ers' first game as a member of the NFL was a home match with the New York Yanks on September 17, 1950. San Francisco lost 21–17. Unlike the Cleveland Browns, who won the championship that year, the 49ers struggled in the NFL, finishing the 1950 season 3–9. In 1951, they would do much better, with a 7–4–1 season and nearly reaching the championship game. The 1952 season saw seven wins and five losses. With a 9–3 record, San Francisco had its best season yet in 1953, but a loss to the Lions kept them from the championship match. Injuries in 1954 caused a 7–4–1 finish. More injuries (notably to RB Hugh McElhenny) caused the 49ers to fall to a losing 4–8 the following year. With former quarterback Frankie Albert taking over as head coach in 1956, the team went 5–6–1. This period was most notable for the destructive on-field antics of LB Hardy Brown, traded from Washington in 1952. Brown established a fearsome reputation for injuring players by ramming them with his shoulder during his five years on the 49ers roster.
In 1957, the 49ers would enjoy their first sustained success as members of the NFL. After losing the opening game of the season, the 49ers won their next three against the Rams, Bears, and Packers before returning home to Kezar Stadium for a game against the Chicago Bears. The 49ers fell behind the Bears 17–7. 49ers owner Tony Morabito collapsed of a heart attack and died during the game. The 49ers players learned of his death at halftime when Coach Frankie Albert was handed a note with two words: "Tony's gone." With tears running down their faces, and motivated to win for their departed owner, the 49ers scored 14 unanswered points to win the game, 21–17. Dicky Moegle's late-game interception in the endzone sealed the victory.
On November 3, 1957, the 49ers hosted the Detroit Lions, a game which has gone down in local lore as featuring arguably the greatest pass play (along with Dwight Clark's "The Catch" in 1981). With 10 seconds remaining, 49ers ball on the Lions 41, Detroit leading 31–28, Y. A. Tittle threw a desperation pass into the end zone, right into the arms of high-leaping R. C. Owens. The play became famously known as the "Alley Oop". Ironically, the two men covering Owens would later become 49ers coaches: Jack Christiansen, head coach of the 49ers from 1963 to 1967, and Jim David, a secondary coach for Christiansen from 1964 to 1966.
The 49ers would end that season with three straight victories and an 8–4 record, tying the Detroit Lions for the NFL Western Division title, and setting up a one-game divisional playoff in San Francisco. The 49ers got off to a fast start, and in the third quarter led 27–7. The Lions, led by quarterback Tobin Rote, who earlier in the season had replaced an injured Bobby Layne, would mount one of the biggest comebacks in NFL history and defeat the 49ers, 31–27. Had they won the game, the 49ers would have hosted the NFL Championship game the following weekend against the Cleveland Browns. As it happened, the Lions wound up beating the Browns 59–14.
For most of the next 13 years the 49ers would be an average team. Frankie Albert resigned as head coach after a 6–6, 1958 season, and was replaced by Red Hickey. He led them to a 7–5 campaign in 1959, and again in 1960. Key players for these 49ers included running back Ken Willard, quarterback John Brodie, and offensive lineman Bruce Bosley.