Guyer is a 2004 graduate of Herndon High School where he was a three-year letter winner in baseball as well as football. In football, he rushed for over 1,000 yards as a tailback for the Hornets in both his junior and senior seasons. As a senior, he set the school single-game touchdown record, scoring seven touchdowns during a 285-yard rushing performance on homecoming night. Guyer helped Herndon break a six-year Northern Region playoff drought, leading the Hornets to a 7-4 season. He was a third team all-state pick as a junior and a second team all-state pick as a senior. In baseball, Guyer is the Hornets' all-time career home run hitter and holds the single-season home run record with eight. He was a part of the Hornets 19-4 Concorde District championship squad in 2002—the last time Herndon won a district title. As a senior, he had 23 RBI, a.483 batting average and was walked 19 times. Guyer attended the University of Virginia, and played college baseball for the Virginia Cavaliers baseball team. In 2006, he played collegiate summer baseball with the Harwich Mariners of the Cape Cod Baseball League. He was selected by the Chicago Cubs in the 5th round of the 2007 MLB Draft.
Professional career
In 2010, playing for the Chicago Cubs Tennessee Smokies affiliate in the Southern League, he was second in the league in batting, third in doubles and slugging percentage, tied for seventh in steals, and ninth in OBP.
Tampa Bay Rays
After the 2010 season, Guyer was included in a trade to the Tampa Bay Rays with Hak-Ju Lee, Chris Archer, Robinson Chirinos and Cubs outfielder Sam Fuld for Matt Garza, Fernando Perez and Zac Rosscup. On May 5, 2011, Guyer was called up to the majors after a successful stint with the Durham Bulls. The next day, in his first major league at bat, he hit a 2-run home run off of Baltimore Orioles rookie pitcher Zach Britton. In doing so, Guyer became the second player in Rays history to hit a home run in his first career at-bat, as well as the first player to ever hit a home run in his first career at-bat in Camden Yards. On May 8, he was optioned back to Durham, for whom for the season he batted.312/.384/.521. Guyer began the 2012 season with Triple-A Durham, hitting.294 with 3 HR and 13 RBI in 22 games before being recalled to Tampa Bay on May 9 after Jeff Keppinger was placed on the restricted list. Guyer played in 3 games with Tampa Bay, going 1-7 with a home run, before he hit the disabled list with a shoulder strain. On May 25, the Rays announced that Guyer was placed on the injured reserve list after undergoing surgery to repair a torn labrum in his left shoulder. Guyer returned to the majors in 2014, and was on the Rays roster on Opening Day. In 2015, he led the American League in being hit by the most pitches, with 24, in 332 at bats. The MLB single-game record for being hit by pitches is three, and Guyer has been the recipient in the two most recent occurrences as of April 21, 2016: on October 2, 2015 vs. the Mets, and on April 21, 2016, vs. the Red Sox. His knack for getting pegged earned him the nickname, "La Piñata."
Cleveland Indians
On August 1, 2016, Guyer was traded to the Cleveland Indians in exchange for prospects Nathan Lukes and Jhonleider Salinas. In 2016 he batted.241/.347/.406 in 293 at bats, and led the major leagues in hit by pitch, with 31. On January 18, 2017, Guyer signed a two-year, $5 million contract with the Indians. The contract also included a $3 million club option for the 2019 season. In 2017 he batted.236/.326/.327 in 165 at bats. In 2018 he batted.206/.300/.371 in 194 at bats. The Indians bought out Guyer's contact for 2019, making him a free agent, on October 30, 2018.
On February 5, 2019, Guyer signed a minor league deal with the Chicago White Sox. He was released on March 23, 2019. On March 26, he re-signed with the White Sox. He became a free agent following the 2019 season.
On February 3, 2020, Guyer signed a minor league deal with the San Francisco Giants. He was released by the Giants in March 2020. He announced his retirement on July 6, 2020.
Personal
On April 2012 it was reported that Guyer was included as a defendant in a $5 million lawsuit with fellow Rays prospect, Matt Bush. The lawsuit was based on Bush being involved in an accident while driving Guyer's Dodge Durango; the lawsuit was settled in 2013.