Highsmith attended Christopher Columbus High School, where he played defensive end and helped his team reach the state championship final in 1982, while receiving All-American, Florida high school Defensive Player of the Year and the Dade County Athlete of the Year honors. He also played basketball and ran track.
Highsmith accepted a scholarship from the University of Miami over offers from Notre Dame University and the University of Michigan. Although he was recruited by Howard Schnellenberger to play defense, he was converted to fullback before his freshman season started. He was a member of the 1983 Hurricanes squad that won the national championship with a 31-30 victory over Nebraska in the Orange Bowl.
In 1984, Jimmy Johnson arrived as the new head coach and named him a starter as a sophomore, rushing for a team leading 906 yards on 146 carries (6.2 average) and 11 touchdowns. One of the hardest working players on the team, he would develop into a complete fullback that could run, block and catch.
As a junior, he registered 451 rushing yards on 117 carries (3.9 average) and 6 touchdowns. In his last year, he was recognized as the nation's best fullback, while posting 442 rushing yards (led the team) on 105 carries (4.2 average) and 8 touchdowns.
Highsmith finished his college career with 1,914 rushing yards (third in school history), 2,935 all-purpose yards (fifth in school history), 25 career touchdowns (tied for fourth in school history) and five 100-yard rushing games (tied for second in school history).
In 1997, he was inducted into the University of Miami Sports Hall of Fame.
Highsmith was selected by the Houston Oilers in the first round (third overall) of the 1987 NFL Draft. He reported to the team after a long contract holdout, that saw him miss 6 months and 6 games. As a rookie, he played in 8 games (3 starts) and registered 106 rushing yards.
In 1988, he started 16 games, rushing for 466 yards (third on the team) on 94 carries for a 5-yard average, while developing into one of the best blocking fullbacks in the NFL. In 1989, he started again 16 games, led the team in rushing with 531 yards and was second on the team with 6 total touchdowns.
During the 1990 season, Jack Pardee became the new Oilers head coach and implemented the run and shoot offense. The team decided that Highsmith wasn't a good fit for new system. On September 3, he was traded to the Dallas Cowboys in exchange for a second round (#38-Darryll Lewis) and a fifth round (#136-Tim Roberts) draft choice.
Although he had started 40 straight games with the Houston Oilers, he had a series of offseason knee surgeries, that had doctors recommending against the Dallas Cowboys acquiring him in 1990, based on a knee condition that could potentially end his career. Head coach Jimmy Johnson, knowing Highsmith from his playing days at the University of Miami, ignored the medical advice and went ahead with the proposed trade on September 3.
He played in 7 games (5 starts) and was the lead blocker for rookie Emmitt Smith, before being placed on the injured reserve list after not being able to fully recover from his previous knee surgery. The next year, he had a contract holdout, that forced him to miss most of training camp. He returned as the third-string fullback and played in only 2 games, before being waived on October 1, 1991.
On October 3, 1991, Highsmith was claimed off waivers by the Tampa Bay Buccaneers. Due to his chronic knee condition, he was released on October 7, 1992.
Highsmith retired after playing in 65 games, posting 283 rushing attempts for 1,195 yards (4.2 avg.) and 7 touchdowns. He also had 42 receptions for 428 yards (10.2 avg.) and 3 touchdowns.
Following his football career, Highsmith became a professional boxer. Over a four-year career, Highsmith amassed a 27–1–2 record in the heavyweight division. Twenty three of those victories came by way of knockout.
Currently, Highsmith resides in Green Bay, Wisconsin with his wife, Denise, and he is the father of five children. In 2012, he accepted a Senior Personnel Executive position in the front office of the Green Bay Packers.
Highsmith's father, Walter Highsmith, was also a successful football player and coach. He, like Alonzo, played for the Oilers in 1972. He also played for the Montreal Alouettes, with and Alonzo playing football and basketball in Montreal as a teenager. Walter was also the former head coach of Texas Southern University and has enjoyed several coaching stints in college football and the CFL. One of Highsmith's sons, also named Alonzo Highsmith Jr., was invited to training camp with the Miami Dolphins, Kansas City Chiefs and the Washington Redskins. Highsmith's cousin, Ali Highsmith, played for the Arizona Cardinals.