Myers attended and played baseball at Wesleyan Christian Academy in High Point, North Carolina. As a freshman, Myers had a .450 batting average and was an all-state third baseman. During his junior year, he went 10–0 as a pitcher. After committing to the University of South Carolina, Myers was drafted by the Kansas City Royals. In 2008, his team won a state championship.

Myers was drafted by the Kansas City Royals as a catcher in the third round, with the 91st overall selection, of the 2009 Major League Baseball draft. Myers signed a contract with the Royals, that included a $2 million signing bonus, in August 2009. Before the draft, Myers had committed to South Carolina during his junior year.

Myers made his debut in professional baseball in 2009, when he played catcher and batted .369 with five home runs in 84 at bats with Royals’ Rookie League affiliates, the Idaho Falls Chukars and the Burlington Royals. Myers began the 2010 season playing catcher for the Burlington Bees of the Midwest League and was named to the Midwest League All Star team. On July 1, 2010, the Royals promoted Myers to the Wilmington Blue Rocks of the Carolina League, a league generally considered more advanced than those in which he had previously played. Myers played catcher and finished the 2010 season batting .315 with a .429 on-base percentage overall, and totaled 14 home runs, 83 runs batted in, and 85 walks between his time in the Midwest League and Carolina League. In 2011, playing for the Class AA Northwest Arkansas Naturals, he batted .254 with eight home runs and 49 RBIs in 99 games. He played primarily outfield in 2012, and was named to appear in the 2012 All-Star Futures Game.

On December 9, 2012, Myers was traded to the Tampa Bay Rays (along with Jake Odorizzi, Patrick Leonard, and Mike Montgomery) in exchange for James Shields, Wade Davis, and a player to be named later (later chosen to be Elliot Johnson). He started the 2013 season with the Triple-A Durham Bulls of the International League. On June 17, Myers was called up to the Rays, for whom he played outfield.

Myers won the AL Rookie of the Year award in 2013, beating teammate and pitcher Chris Archer and Detroit shortstop José Iglesias. In spite of the fact that he did not join the Rays until their 70th game on June 18, Myers led AL rookies with a 53 RBIs in the 88 games he played. The last player to lead AL rookies in RBIs in fewer than 90 games was Hoot Evers playing for the Detroit Tigers in 1946, when he had 33 in 81 games. He also became the first-ever hitter to win the award in under 100 games.

Myers entered 2014 as the Rays’ everyday right fielder. On May 4, Myers hit his first career inside-the-park home run. During a game against the Boston Red Sox on May 30, Myers collided with Desmond Jennings while attempting to catch a fly ball, resulting in a stress fracture in Myer’s right wrist which required a cast and significant rehab time. Myers returned to the club on August 20, initially slotted as a DH before returning to the field.

In 2014, he batted .222/.294/.320 with six home runs and 35 RBIs in 325 at bats.

On December 19, 2014, the Rays traded Myers, Ryan Hanigan, and Jose Castillo to the San Diego Padres as part of a three-team transaction, in which the Padres traded Jake Bauers, Burch Smith, and René Rivera to the Rays, the Padres traded Joe Ross and Trea Turner to the Washington Nationals, and Washington traded Steven Souza and Travis Ott to Tampa Bay.

In 2015, he batted .253/.336/.427 with eight home runs and 29 RBIs in 225 at bats.

Myers’ parents are Eric and Pamela Myers. He has a younger brother named Beau who pitched to him in the 2016 Home Run Derby. He married Maggie Reaves on November 3, 2018.

On January 17, 2017, Myers signed a six-year $83 million extension with the Padres.

Myers hit for the cycle on April 10, 2017 at Coors Field against the Colorado Rockies. It was the second cycle in Padres history. On September 2, a commemorative bobblehead celebrating his accomplishment was handed out to fans at Petco Park.

Over the offseason before the 2019 season, the Padres signed superstar third baseman Manny Machado, which moved Wil Myers to the outfield. Due to the emergence of corner outfielders Franmil Reyes and Hunter Renfroe in 2018 while Myers was injured, he was also involved in trade rumors, but nothing materialized. On opening day, Myers hit the first home run of the Padres season. On April 15, Myers hit his 100th career home run in a home loss to the Rockies. However, 2019 was considered a lost season for Myers, as he struck out in well over 30% of his plate appearances, struggled mightily in “clutch” situations, and fell out of favor with Green and management, while also being booed at home by San Diego fans at times.

In the 2020 season shortened by COVID-19, Myers played in 55 of the 60 games and batted .288/.353/.606 with 15 home runs and 40 RBIs.