Born in Philadelphia, Pennsylvania, Dykes batted and threw right-handed. He started his major league career on May 6, 1918 as a second baseman for the Athletics, and served in the wartime Army after the season ended. He spent most of 1919 in the minor leagues after reporting out of shape in spring training, but quickly became one of manager Connie Mack's favorite players with his defensive versatility and easygoing manner, and remained with the club for the next 14 years, primarily at third base. With powerful wrists and reputedly the sport's best throwing arm, he took advantage of Shibe Park's friendly dimensions to finish among the league leaders in home runs in 1921 and 1922, and batted .312, .323 and .324 in 1924, 1925 and 1927, being named team MVP in 1924 and placing eighth in the league MVP vote in 1927. In one 1927 game, he played every position exccept catcher and left field, even appearing as a relief pitcher. In 1929 he batted .327 and was ninth in the AL in slugging average as the Athletics won their first pennant in 15 years. He capped the season by hitting .421 in the World Series against the Chicago Cubs; in Game 4, he had two hits and 3 runs batted in in a 10-run seventh inning as Philadelphia overcame an 8-0 deficit, and they won the Series in five games.

In 1930 Dykes batted .301 as the Athletics repeated as champions; in the 1930 World Series against the St. Louis Cardinals, he batted only .222, but drove in the winning run in Game 1 and had a 2-run home run in the final Game 6, a 7-1 victory. In 1931 his batting average dropped to .273 as Philadelphia won its third straight pennant; but they lost their rematch with the Cardinals as he hit .227 in the 7-game Series. At the end of the 1932 season, after a disappointing year for the team, Dykes was sold to the White Sox together with Al Simmons and Mule Haas in order to keep the franchise afloat during the Depression; with the Sox, he was selected to the first two All-Star Games in 1933 and 1934. Early in the latter season he succeeded Lew Fonseca as White Sox manager; he was a player-manager from 1934 through 1939, and after retiring as a player continued as manager until early 1946. Prior to his retirement as a player, he was the last active major leaguer who had played in the 1910s. In 22 seasons, Dykes was a career .280 hitter with 2256 hits, 108 home runs, 1108 runs and 1071 RBI in 2282 games, along with 453 doubles and 90 triples. His 115 times being hit by a pitch ranked second in AL history behind Kid Elberfeld's 142, and his 850 strikeouts ranked fourth in major league history. His Athletics team records of 1702 games and 6023 at bats were broken in the 1970s by Bert Campaneris after the franchise relocated to Oakland.

As a manager, he proved more combative and argumentative than he had been as a player, and was often fined and suspended; his 62 ejections were among the all-time top ten when he retired. After Ted Lyons replaced him as the Chicago manager, Dykes managed two years in the minor leagues with the Hollywood Stars. He returned to the majors in 1949 as a coach with the Athletics; one year later, the legendary Mack retired after 50 years managing his team, naming Dykes to the formidable task as his successor for the 1951 season. Mack, who also owned the club, maintained his position as president of the club and Dykes remained as manager until the end of the 1953 pennant race.

Named the Baltimore Orioles' first manager in 1954 after that franchise relocated from St. Louis, Dykes left in a team reorganization which ended with Paul Richards becoming both field and general manager in 1955. Dykes then ended his 35 years in the American League when he became a coach with the National League's Cincinnati Redlegs, leading them as interim manager for part of 1958. But he came back to the AL as manager of the Detroit Tigers in 1959. At that point, Frank Lane, then general manager of the Cleveland Indians and famous for his numerous transactions, sent Joe Gordon to Detroit and brought Dykes to Cleveland in a rare trade of managers. Dykes managed the Indians from 1960-61.

In 21 seasons as a manager, Dykes compiled a 1406-1541 record; he never won a pennant, and his highest finish was third place. He ended his 44-year major league career in 1964 after completing three seasons of coaching for the Milwaukee Braves and the Athletics, who had relocated to Kansas City by that time. Although he had a different style of managing his teams, Dykes had authority, was testy and combative; he liked to make use of his entire roster and was regarded as a motivator of players.

Dykes died in Philadelphia at age 79.