Growing up in Kentucky, Marcum's professional career started after Bill Neal, the manager of the Louisville Colonels, saw him pitching and signed him to a contract.

He spent the next two years with the Athletics as one of their main starting pitchers, posting records of 14–11 in 1934 and 17–12 in 1935, a season in which he received votes for the American League Most Valuable Player.

"[2] In 1927, Bill Neal, who managed the Louisville Colonels of the Class AA American Association, saw Marcum pitching and signed him to a contract.

Reports indicate that Marcum spent much of the 1928 season pitching batting practice for Louisville and playing occasional games as an outfielder.

[1] In 39 games for the Aviators, Marcum had a 9–19 record, a 5.37 earned run average (ERA), 109 strikeouts, 83 walks, and 326 hits allowed in 285 innings pitched.

[4] Despite this, manager Allen Sothoron thought Marcum was too slow to reach the major leagues as an outfielder, and he used him strictly as a pitcher the following season.

[4] Though the Colonels finished last in the American Association's East Division, Marcum's 20 wins were third in the league, behind only Paul Dean's 22 and Bill Lee's 21.

[1][6] During the 1933 season, Earle Mack, a scout for the Philadelphia Athletics, attended a series between Louisville and the St. Paul Saints, attempting to find his team another pitcher.

The hurler he went to see had just injured his foot and was not throwing as hard as normal, but Mack was impressed with Marcum and returned a favorable report.

Around this time, the Colonels mailed a letter to all 16 of the major league teams, offering Marcum's contract to the highest bidder.

Philadelphia won the bidding on August 20 with an offer of either $25,000 or $30,000, later sending Jim Peterson to the Saints to complete the transaction on September 30.

[1][7][8] Marcum made his major league debut on September 7 at Philadelphia's Shibe Park, holding the Cleveland Indians to five hits and pitching a shutout in a 6–0 victory.

He hit a game-tying single against John Whitehead, left the game in favor of a pinch runner, and returned to the clubhouse as Philadelphia rallied to win 5–3.

[1][20][21] On July 23, he was "invincible with men on base", according to the Associated Press, as he threw an eight-hit shutout in a 2–0 victory over the White Sox.

[22] During the season, Marcum set career bests in many categories, including wins (17), ERA (4.08), strikeouts (99), and innings pitched (242+2⁄3).

[10] His 17 wins were the seventh-best total in the AL, and they easily led the last-place Athletics, as no other Philadelphia pitcher won more than nine games.

Dozier Jr., sports editor of the Sarasota Herald, wrote before the 1936 season that the Red Sox would be "bolstered by the purchase of such stars as Jimmy Foxx, Heinie Manush, and Johnny Marcum.

[26] The start of his season was delayed slightly due to a sore arm, treated by a tonsillectomy, a common remedy of the period.

[1] Following the season, in its assessment of Marcum and several other veterans the Red Sox had acquired over the years, the Courier-Post reported that "none has set the world on fire since going to Boston".

[10] On June 2, in an exchange of two pitchers in the midst of poor seasons, Marcum was traded to the White Sox for John Whitehead.

[1][10] After allowing one run in 7+1⁄3 innings of relief in his first game with the White Sox, Marcum won three appearances in a row, from June 23 through July 4.

[37] In a relief outing against the Detroit Tigers on August 9, he was hit above the right eye by a line drive off the bat of Hank Greenberg.

[37][38] His final appearance came against the Browns in the first game of a September 30 doubleheader; he pitched five scoreless innings of relief but had a no decision in a 5–1 loss.

His combined totals between the teams were a 5–8 record, a 6.60 ERA, 46 strikeouts, 29 walks, and 191 hits allowed in 137+2⁄3 innings pitched over 31 games (12 starts).

[10] The Browns reacquired Marcum's contract on December 15, 1939, but they assigned him to their top affiliate, the American Association's Toledo Mud Hens, for the next three seasons.

[1] He pitched for the Borger Gassers of the Class C West Texas-New Mexico League in 1947, but after posting a 1–4 record and an 8.23 ERA, he retired in May.

[42] Eddie Brietz of the Associated Press reported that his fellow players considered him the "laziest guy in the American League", due partly to his habit of picking up his teammate's bat at the plate rather than carrying one out from the dugout when it was time for him to hit.