He played in Major League Baseball (MLB) for the Pittsburgh Pirates (1994–1998), Chicago Cubs (1999–2002 and 2008), New York Yankees (2004), and Philadelphia Phillies (2005–2007).

Lieber attended the University of South Alabama, helping them win the Sun Belt Conference Championship.

He was selected by the Chicago Cubs in the ninth round of the 1991 Major League Baseball (MLB) draft, but he did not sign.

He also appeared in seven games (six starts) for the Baseball City Royals of the A-Advanced Florida State League, posting a 3–3 record, a 4.65 ERA, 19 strikeouts, eight walks, and 45 hits allowed in 31 innings pitched.

Lieber began the season with Wilmington, posting a 9–3 record, a 2.67 ERA, 89 strikeouts, nine walks, 125 hits allowed, and 114+2⁄3 innings pitched in 17 games (16 starts).

[4][5] On July 31, seeking pitching help as they contended for the playoffs, the Royals traded Lieber and Dan Miceli to the Pittsburgh Pirates for their closer, Stan Belinda.

[6] The Pirates assigned Lieber to the Southern League's Carolina Mudcats; in six starts, he had a 4–2 record, a 3.97 ERA, 28 strikeouts, 10 walks, and 39 hits allowed in 34 innings pitched.

[4] Lieber made three starts with the Mudcats in 1994, posting a 2–0 record, a 1.29 ERA, 21 strikeouts, two walks, and 13 hits allowed in 21 innings.

He also made three starts for the Buffalo Bisons of the Triple-A American Association, posting a 1–1 record, a 1.69 ERA, 21 strikeouts, one walk, and 16 hits allowed in 21+1⁄3 innings pitched.

[4] Lieber was called up by the Pirates in May 1994 to join their starting rotation, replacing Randy Tomlin, who was moved to the bullpen.

Like many of the young Pirates' pitchers that year, Lieber struggled; he was optioned to the Calgary Cannons of the Triple-A Pacific Coast League on June 18 after going 2–7 with a 7.48 ERA.

[12] In 21 games (12 starts), Lieber compiled a 4–7 record, a 6.32 ERA, 45 strikeouts, 14 walks, and 103 hits allowed in 72+2⁄3 innings pitched.

[15] In 51 games (15 starts) in 1996, Lieber posted a 9–5 record, a 3.99 ERA, 94 strikeouts, 28 walks, and 156 hits allowed in 142 innings pitched.

On June 30, he threw his only complete game of the year, striking out 10 while allowing one run on five hits in a 3–1 victory over the Chicago White Sox.

He was third in the NL in losses (behind Mark Leiter's 17 and teammate Steve Cooke's 15); however, he tied Mike Hampton for the most runs batted in by a major league pitcher with eight.

Lieber had an 8–13 record with a 3.90 ERA before getting placed on the disabled list (DL) for the first time in his career on August 21 due to a left oblique muscle strain.

[5][21] In 29 games (28 starts), Lieber posted an 8–14 record, a 4.11 ERA, 138 strikeouts, 40 walks, and 182 hits allowed in 171 innings pitched.

[29] In 35 starts (tied for the NL lead with Randy Johnson, Kevin Millwood, Tom Glavine, and Greg Maddux), Lieber had a 12–11 record, a 4.41 ERA, and 54 walks.

[31] On May 24, he one-hit the Cincinnati Reds, 3–0, ending the team's NL-record streak of 208 games in a row without being shut out, throwing just 78 pitches.

[33] In 34 starts, Lieber recorded a career-high 20 victories to go with just six losses, posted a 3.80 ERA, and struck out 148 as opposed to 41 walks.

[35] Due to the terrorist attacks of Sept. 11, 2001 and the week-long break in the baseball season, Lieber became the first Cubs pitcher to start consecutive contests since Scott Sanderson on May 18 and May 20 of 1986.

[38] On August 1, facing the San Diego Padres, Lieber allowed two runs in seven innings but received a no-decision in an 8–7 Cubs' victory.

[39] He was placed on the DL with right elbow tendinitis the next day, and he underwent Tommy John surgery on August 8, ending his season.

[5] He still managed to tie Randy Wolf, Brett Tomko, Pedro Astacio, and teammate Matt Clement for tenth in the league with three complete games.

[5][49] Dave Caldwell of the New York Times wrote on September 3 that Lieber would "probably end up in the bullpen" in the playoffs, but less than a month later, Mark Feinsand of MLB.com wrote that Lieber "has suddenly become one of the most important cogs in the Yankees' postseason machine" due an injury to Kevin Brown and late-season struggles by Vázquez.

[53] In Game 2 of the AL Championship Series against the Red Sox, Lieber allowed one run and three hits in seven innings, earning the win in a 3–1 victory.

[73][74] He appeared in his final major league game on September 5, giving up four runs in two innings in a 10–2 loss to Cincinnati.

[75] In 26 games (one start), Lieber posted a 2–3 record, a 4.05 ERA, 27 strikeouts, six walks, and 59 hits allowed in 46+2⁄3 innings pitched.

Lieber was not a hard thrower (his fastball was in the low 90 mph range); he relied on controlling his pitches to have success.