Skiles holds the NBA record for assists in one game, with thirty. In 1990-91 he won the NBA Most Improved Player Award.In 1982, Skiles led Plymouth High School to the Indiana State Championship. Plymouth won the state title with a 75-74 double overtime victory over heavily favored Gary Roosevelt. In that game, Skiles scored 39 points to lead the Pilgrims past the Roosevelt Panthers; his long field goal, that was well beyond where the current three-point line is (no three-point shot existed in 1982), as time expired sent the game into overtime. Many consider the game one of the most memorable finals from the era of classless basketball in Indiana, when all high schools in the state competed for a single championship regardless of enrollment.

Skiles attended Michigan State University, where in his senior season he was a First Team All-America selection as well as the Big Ten Conference MVP and scoring champion. He left MSU as its all-time career scoring leader (2,145 points) and still holds the Spartans' record for most points scored in a season (850). During his senior season, Skiles committed a parole violation on an earlier marijuana conviction, and served a brief jail sentence. He has been clean ever since.[citation needed]

The Milwaukee Bucks made Skiles the 22nd overall selection of the 1986 NBA Draft. In ten seasons, he played for the Bucks (1986�87), Indiana Pacers (1987�89), Orlando Magic (1989�94), Washington Bullets (1994�95), and Philadelphia 76ers (1995�96).

On December 30, 1990, Skiles racked up 30 assists in Orlando's 155-116 victory over the Denver Nuggets, breaking Kevin Porter's record. He averaged 17.2 points and 8.4 assists per game that season, doubling his marks from the previous year and earning the NBA Most Improved Player award.

In 1996, nursing a serious shoulder injury, Skiles left the U.S. for the European league and joined PAOK in Thessaloniki, Greece. At PAOK, expectations were high for the new arrival from the NBA. Midway through the season, however, injuries and contract problems with key players threatened to devolve into a disastrous season for PAOK and French coach Michel Gomez. Still struggling with injury himself, increasingly at odds with his coach, and fighting a custody battle in the U.S. for his two children, Scott asked to be released from his contract. Instead, President Lakis Alexopoulos fired Gomez and offered Skiles the job. Despite lacking three of their top players due to injury, Skiles led PAOK to a winning record as coach in the remainder of the '96-'97 season, and an unexpected 3rd place finish in the league tournament.

The following year Scott Skiles returned to the NBA as an assistant coach with the Phoenix Suns and was later elevated to head coach (1999). Under Skiles, Phoenix compiled a winning record (.595) and made the playoffs in two of his three years, including a first-round win over the defending NBA champion San Antonio Spurs in 2000. In 2003, after a two-year absence from the game, Skiles came to the Chicago Bulls as head coach where he focused on improving the young Bulls' defense and developing greater consistency in a talented but underachieving team. In the first full year under his direction, Chicago limited its opposition to an NBA-best .422 field goal percentage and held their opponents to a franchise record and NBA season-high 26 straight games below 100 points. Scott was named NBA Eastern Conference Coach of the Month for January 2005 after guiding the Bulls to an NBA best 13-3 mark in that month.

In 2006, Skiles led his Bulls to a 41-41 record (earning a 7th seed in the playoffs) and faced the Miami Heat (the 2nd seed) in the first round of the playoffs, losing in six games.