Samardzija grew up in Valparaiso, Indiana, where he attended Valparaiso High School, and was a letterman in football, basketball, and baseball. In football, he was a three-time first team All-State honoree, and was twice named the team’s Most Valuable Player. After his junior year, he was invited to participate in the Indiana football All-Star game. In baseball, he was a first team All-State honoree. He graduated from Valparaiso High School in 2003.

In football, he was a reserve for his first two seasons, catching a total of 24 passes. He first started at the 2004 Insight Bowl at the end of his sophomore season. He emerged as a star in the 2005 season, ending the regular season with 77 catches – 15 of them for touchdowns – for 1215 yards and making numerous All-America Teams.

Samardzija was twice selected as one of the three finalists for the Fred Biletnikoff Award, for the nation’s top wide receiver in both 2005 and 2006. Although initially planning to play both in the NFL and MLB, Samardzija announced after being selected in the Major League Draft that he would take his name out of the NFL Draft and play baseball.

Samardzija set single-season school records in both receiving yardage and touchdown receptions. He caught a touchdown pass in each of Notre Dame’s first eight games in 2006, giving him the school record for consecutive games with a touchdown reception. He made 78 catches for 1,017 yards and 12 touchdowns in 13 games in the 2006 season to finish as the all-time Fighting Irish leader in reception yards with 2,593. He made the Football Writers Association of America All-America Team following the 2006 season.

On January 19, 2007, Samardzija announced he would forgo the NFL Draft and commit to a baseball career. Samardzija signed a five-year deal to play baseball with the Chicago Cubs. The deal had a no-trade clause and a club option for a sixth and seventh year. If the club option were exercised, the total value of the deal would have been $16.5 million. The deal included a $1 million signing bonus.

On June 23, 2008, Samardzija was promoted to Triple-A Iowa after posting a 3–5 record in Tennessee with a 4.86 ERA. In his career in Triple-A Iowa, he has posted a 4–1 record and a 3.13 ERA, with 40 strikeouts and 16 walks.

On July 25, 2008, Samardzija was called up to join the bullpen of the Chicago Cubs to replace Kerry Wood, who was placed on the DL.

He made his MLB debut the same day against the Florida Marlins, striking out the first batter he faced in the 7th inning. Chicago Cubs Manager Lou Piniella was impressed with Samardzija’s major league debut, saying he may never see the minors again. On July 27, 2008, Samardzija recorded his first career major league save against the Florida Marlins.

In 2009, Samardzija was optioned to the Triple-A Iowa Cubs after failing to make the team out of spring training. However, he was quickly called back up only a few games into the season. He quickly returned to Des Moines to pitch for the Iowa Cubs, after posting an 8.10 ERA in 5 appearances. He made his first major league start on August 12 against Pedro Martínez of the Philadelphia Phillies, a 12–5 loss.

In March 2010, Samardzija returned to the Cubs and pitched his first game in exhibition on March 13, 2010. He pitched in four regular season games in April and compiled an 18.90 ERA before being sent back down to the Triple-A Iowa Cubs in order to make space for Ted Lilly on the Cubs roster.

In 2011, Samardzija made the opening day roster as a reliever. During the 2011 season Samardzija, statistically had his best season posting an 8–4 record and an ERA of 2.97

In 2012, Samardzija was named a starter in the Cubs rotation and was solid going 9–13 with a 3.81 ERA and 180 strikeouts.

On March 3, 2013, Samardzija was named the opening day starter. He threw his first major league shutout on May 27, 2013 against the Chicago White Sox, allowing two hits and two walks. He was named National League Co-Player of the Week for August 19–25, 2013, after recording a 2–0 record and 1.59 ERA in 17 innings pitched.

He began 2014 as a hardluck pitcher. He set a major league record for lowest ERA (1.46) by a winless pitcher through his first 10 starts. The 1.46 ERA was the latest league-leading ERA by a winless pitcher since Bruce Sutter’s 0.89 ERA on June 7, 1977. Samardzija won his eleventh start of the season by striking out a season-high 10 San Francisco Giants. On June 18, 2014, the Cubs offered Samardzija a five-year, club friendly deal that included multiple option years, which he rejected.

On July 6, 2014, he was revealed as a National League All-Star, but was not eligible to play because he was traded to an American League team.

On July 5, 2014, Samardzija, along with Jason Hammel, was traded to the Oakland Athletics in exchange for top shortstop Addison Russell, pitcher Dan Straily, outfielder Billy McKinney, and cash. In his debut on July 6, he went seven innings with five strikeouts, allowing one run and four hits.

On December 9, 2014, the Athletics traded Samardzija along with Michael Ynoa to the Chicago White Sox in exchange for Marcus Semien, Chris Bassitt, Rangel Ravelo and Josh Phegley. Samardzija and the White Sox avoided arbitration by agreeing to a one-year deal for $9.8 million on January 16, 2015.

Samardzija made his first start for the White Sox on April 6, 2015, during opening day against the Kansas City Royals. He allowed 5 runs including a home run by Alex Ríos in 6 innings as the White Sox lost to the Royals, 10–1. During another game against the Royals on April 23, Samardzija was one of five players to be ejected for his role in a bench-clearing brawl. On April 25, Samardzija was suspended 5 games. On July 9, he pitched a complete game shutout and allowed only four hits in a 2–0 victory over the Toronto Blue Jays at US Cellular Field. This was his first complete game shutout victory for the White Sox and the second of his major league career. On September 21, Samardzija pitched a complete-game one-hit shutout against the Detroit Tigers on only 88 pitches; the only baserunner was Victor Martinez, who singled to lead off the fifth inning, and no batter’s count went to three balls. Despite the strong finish, Samardzija tied for the American League lead in home runs allowed (29) and led the league in earned runs allowed (118). Overall, Samardzija finished 11–13 with a 4.96 ERA. After the season, Samardzija revealed that had been inadvertently tipping his pitches, leading to his poor performance.

On December 9, 2015, Samardzija signed a five-year, $90 million contract with the San Francisco Giants. He earned his first win as a Giant on April 13, 2016, yielding only two earned runs and six hits in 8 innings pitched at Coors Field. Samardzija earned his first home win as a Giant on April 22, pitching 7⁄3 innings while giving up only one earned run against the Miami Marlins. Samardzija also matched his career-high for a season of 3 RBIs in the game. In his first season as a Giant, Samardzija was fifth in the National League with 203.1 innings pitched and finished 2016 with a 12–11 record and a 3.81 ERA. The 12 wins were a career high and it was his first winning season since he became a full-time starter in 2012.

In 2019 he was 11–12 with 3.52 ERA, as he started 32 games (8th in the NL) and pitched 181.2 innings. He was 10th in the National League in WHIP (1.108) and in hits per 9 innings pitched (7.544).

On September 26, 2020, Samardzija was designated for assignment by the Giants and placed on release waivers. In 2020 for the Giants, Samardzija pitched to an 0–2 record with a 9.72 ERA, allowing 18 earned runs over 16.2 innings pitched.