Seager elected to stay in-state, playing college baseball at the University of North Carolina, where he had a career .353 batting average with 17 home runs, 66 doubles and 167 RBI. In 2008, he set a school record for doubles in a season (30), was a semifinalist for the Golden Spikes Award, and was named to the watch list for both the Dick Howser Trophy and the Brooks Wallace Award.

On July 6, 2011, Seager had his contract purchased by the Mariners. He hit his first Major League home run on August 19, 2011, against the Tampa Bay Rays at Tropicana Field, and finished the year with a .258 batting average, 3 home runs and 13 RBI in 53 games.

Seager and his wife, Julie, married in 2011. They have two daughters and a son.

In 2012, his first full MLB season, Seager hit .259 with 20 home runs and 86 RBI in 155 games.

Seager is the eldest of three sons born to Jeff and Jody Seager. His brother Corey was selected by the Los Angeles Dodgers in the first round of the 2012 Draft, while brother Justin was selected by the Mariners in 2013.

On June 4, 2013, he hit a grand slam against the Chicago White Sox in the 14th inning. It was the first time in MLB history that a player hit a game-tying grand slam in extra innings. He finished 2013 with a .260 batting average, 22 home runs and 69 RBI in 160 games.

On April 23, 2014, he drove in five runs to avoid a sweep against the Houston Astros. He hit a two-run home run in the seventh inning to cut the Astros lead to 3–2, and hit a walk-off three-run shot in the bottom of the ninth, allowing the Mariners to win 5–3. The first walk-off hit of his career, his performance earned him an April Co-Player of the Week Award, shared with José Abreu of the White Sox. On June 2, Seager went 4–4 with a double, two triples and a three-run home run against the New York Yankees. The first Mariner to accomplish the feat, he became the first MLB player with two triples and at least one double and homer in a game since Hal Breeden for the Montreal Expos in 1973. On June 15, he went 4–4 with two singles and two doubles and three RBI. On July 7, he was named to his first All-Star team as an injury replacement for Toronto Blue Jays player Edwin Encarnación. He finished 2014 with a .268 batting average, 25 home runs and 96 RBI in 159 games.

On December 2, 2014, the Mariners finalized a 7-year, $100 million contract extension with Seager. In 2015, he hit .266 with 26 home runs and 74 RBI in 161 games.

On April 25, 2016, he hit his 100th career home run in a game against Houston. He finished 2016 with a.278 batting average, 30 home runs and 99 RBI in 158 games and he and his brother, Corey, made history by becoming the first pair of brothers in major league history to each hit 25 or more homers in the same season. On defense, he led the major leagues in fielding errors, with 18.

In 2017, he hit .249 with 27 home runs and 88 RBI in 154 games, his sixth consecutive season with at least 20 home runs and at least 154 games played.

On April 7, 2018, he reached 1,000 career hits against the Minnesota Twins. Seager continued his streak of seasons with 20 or more home runs and at least 154 games played, hitting 22 home runs with 78 RBIs in 155 games but hit a career low .221 in the process.

In 2019, during a spring training game, Seager sustained an injury to his left hand while attempting a diving play on a ball. He was later diagnosed with a hand injury and would require hand surgery that would sideline him for 8 to 10 weeks. He missed 53 games before returning to the lineup in late May 2019. On August 13, 2019, in an 11-6 victory over the Detroit Tigers, Seager became the 11th Mariner to hit 3 home runs in a game, and the first since 2010; the third home run was a ricochet off the glove of Goodrum when a teammate collided with him near the wall. In 106 games, Seager hit .239 with 23 home runs and 63 RBI, extending his streak of consecutive seasons of 20 or more home runs to eight.

On August 5, 2020, in a game against the Los Angeles Angels of Anaheim, Seager hit his career 200th home run. On August 17, Kyle faced his brother, the Dodgers Corey Seager, for the first time in an MLB game and both homered in the game, becoming the first pair of brothers to homer in the same game since César and Felipe Crespo did it on June 7, 2001.

In 2020 he batted .241/.355/.433 with 9 home runs and 40 RBIs, and led the AL with 6 sacrifice flies.