[4] Horlen attended high school contemporaneously with future major league pitcher Gary Bell, graduating one year later.

He was named to the American Baseball Coaches Association All-America second team, and first-team All-Big Eight, as he helped lead Oklahoma State to victory in the 1959 College World Series.

[7][8] He was named to the All-Tournament Team, with a 2-0 record (pitching two complete games), 1.99 ERA, and tournament leading 18 strikeouts.

[9] The next season he pitched in Single-A for the Charleston White Sox, and had a 7–5 win–loss record with a 2.93 earned run average (ERA).

[9] In 1964, he earned a spot in the starting rotation, posting a 13–9 record and setting career bests in ERA (1.88; second in the American League only to Dean Chance's 1.65[11]) and strikeouts (138).

[12][7] Three of the top 10 ERA pitchers in the American League were White Sox (Horlen, Gary Peters, and Juan Pizarro),[13] but the team batting average was .247, with only 106 home runs.

[15][4] In 1966, he led the league in wild pitches (14), was sixth in hit batsmen (six), and was second in ERA (2.43) behind teammate Gary Peters.

[4][16] Horlen finished the 1967 season with a 19–7 record and led American League pitchers with a 2.06 ERA and six shutouts, was second in W-L percentage (.731), fourth in wins, complete games (13), and walks/9 IP (2.02), and 7th in innings pitched (258).

However, on September 27, which would be known by fans as "Black Wednesday",[21] the lowly Kansas City Athletics swept a doubleheader from the White Sox and effectively eliminated Eddie Stanky's "Hitless Wonders" (the White Sox led the Majors with a 2.45 earned run average but also posted a .225 batting average, with no regular batting above .250[22]) from pennant contention.

[28] Horlen finished runner-up to Jim Lonborg, the star of the Red Sox staff, in the American League Cy Young Award balloting, and fourth in MVP voting, won by Boston's Carl Yastrzemski.