On March 13, 1960, the league's 12 owners unanimously approved the Cardinals' move to St. Louis, ending the team's 62-year history and 40 NFL seasons in Chicago.

[1] In addition to the NFL's blessing, the Bidwills sought permission from the long-established baseball team in their new city to share the "Cardinals" nickname.

For decades, the NFL had demanded a modern stadium as a condition for returning to the city, until the prospect of competition with the AFL compelled them to approve the Cardinals' move in exchange for a pledge to eventually build a new venue.

However, it was clear the team would be playing for at least a few years not only in an antiquated ballpark not designed for football with poor and outdated infrastructure and in a neighborhood that had fallen into disrepair.

However, the Cardinals were then forced to play what was supposed to be their home opener against the Baltimore Colts at Memorial Stadium when their landlords reached the World Series.

Starting quarterback Charley Johnson struggled most of the season with a shoulder injury and defensive leader Larry Wilson missed games with broken hands.

They were in first place in the Eastern Conference with a 7-1–1 record, but Johnson suffered a season-ending injury against the Giants and the Cardinals lost four of their last five games leaving them out of the playoffs.

The 1966 season saw the debut of first-round draft pick Johnny Roland who gained 908 yards from scrimmage and was named NFL Rookie of the Year.

This opened the door for Jim Hart who was signed as an undrafted free agent out of Southern Illinois University the previous season.

St. Louis still beat Cleveland at home to complete the season sweep and end the year with a 9–4–1 mark, which was better than two other NFL playoff teams but a half game behind the Browns.

They posted three consecutive shutouts in November, blanking the Oilers, Patriots, and the Cowboys, the latter a 38–0 victory on Monday Night Football in the Cotton Bowl.

But St. Louis collapsed down the stretch, losing December games to the New York Giants, Detroit Lions, and Washington Redskins to finish 8–5–1 and out of the playoffs.

The playoff game against the Los Angeles Rams was a disaster: Lawrence McCutcheon set an NFL playoff record by rushing for 202 yards, and Jack Youngblood and Bill Simpson returned interceptions for touchdowns, staking the Rams to a 28–9 halftime lead en route to a 35–23 victory at the Los Angeles Memorial Coliseum.

Team stars from the 1970s included Wehrli, wide receiver Mel Gray, and running backs Terry Metcalf and Jim Otis.

The Cardinals experienced several years of notoriously poor drafts and unfortunate personnel moves in the late 1970s, typified by the first-round selection of kicker Steve Little, who was paralyzed in a 1980 automobile accident, and hiring Wilkinson in 1978.

The heart of this squad was the prolific trio of quarterback Neil Lomax, wide receiver Roy Green, and running back Ottis Anderson.

In the strike-shortened 1982 season, the Cardinals finished 5–4, which was nevertheless good enough to qualify for the team's first postseason appearance since 1975 due to the expanded 16-team playoff field.

St. Louis finished 1983 at 8–7–1, including victories over the eventual Super Bowl champion Los Angeles Raiders and the Seattle Seahawks, who lost to the Raiders in the AFC championship game; the team also lost in meetings between the two NFC Championship game participants, the NFC champion Washington Redskins and their opponent, the San Francisco 49ers.

While NFL teams increasingly demanded modern football-specific venues, there was little political will at the time to publicly finance a new football-only stadium for the St. Louis Cardinals.

The overall mediocrity of the Cardinals, combined with an stadium now seen as inadequate,[6] caused game attendance to dwindle, and once again the Bidwills decided to move the team, this time to either Baltimore, Phoenix, or Jacksonville.

[7] Nonetheless, Cardinals fans were unhappy at losing their team, and Bill Bidwill, fearing for his safety, stayed away from several of the 1987 home games.

Due to the NFL's scheduling rotation, the Arizona Cardinals only played one game in St. Louis prior to 2002, a 20-17 win over the Rams at Trans World Dome.

With the Rams' move back to Los Angeles, St. Louis became the first city to have lost two NFL teams to the western United States.

Dierdorf, Smith, Wehrli and Wilson were members of the St. Louis Football Ring of Fame in The Dome at America's Center when the Rams played there from 1995 to 2015.