On June 25, 2009, Blair was selected by the San Antonio Spurs with 37th overall pick in the 2009 NBA draft. His stock fell because of questions surrounding his durability and knee surgeries. On July 17, he signed a four-year deal with the Spurs. In his first NBA game, he posted a double-double with 14 points and 11 rebounds in 23 minutes against the New Orleans Hornets on October 28, thus becoming just the third Spurs rookie, along with David Robinson and Tim Duncan, to record a double-double in his debut with the team.
He later recorded 28 points and 21 rebounds in 31 minutes against the Oklahoma City Thunder on January 13, 2010, becoming first NBA rookie since Tim Duncan in the 1997–98 season to post a 20-20 game. In the team’s final regular season game, he recorded 27 points, a season-high 23 rebounds, 4 assists and 3 steals in 37 minutes against the Dallas Mavericks on April 14, becoming the first rookie since Joe Smith in 1995–96 to post two 20-20 games in the same season. Blair also participated in the 2010 Rookie Challenge, where he recorded 22 points and 23 rebounds. Sacramento Kings guard Tyreke Evans won the game MVP award, but graciously offered to share it with Blair. At the season’s end, he was named to the NBA All-Rookie Second Team and was the only Spurs player to appear in all 82 regular season games. He started 23 games, averaging 7.8 points and 6.4 rebounds in 18.2 minutes per game. He was also the top-ranked rookie in field goal percentage (.556), and was second in rebounding.
In 2010–11, Blair appeared in 81 games, including 65 starts, averaging 8.3 points, 7.0 rebounds, 1.17 steals, and 1.0 assist in 21.4 minutes per game. He scored in double figures 28 times, including two 20-plus games, and posted 17 double-doubles, with 12 of those coming after the turn of the new year.