Sharapova started 2006 by losing in the semifinals of the Australian Open in three sets to Henin, also losing a rematch several weeks later at the Dubai Tennis Championships, having defeated former world no. 1 Martina Hingis and world no. 3 Lindsay Davenport in earlier rounds of the tournament.

Sharapova claimed her first title in nine months at the Tier I tournament in Indian Wells, defeating Hingis in the semifinals and Elena Dementieva in the final. The following fortnight, she reached the final in Miami before losing to Kuznetsova.

Missing the entire clay-court season with injury, Sharapova returned for the French Open. There, after saving match points in defeating Mashona Washington in the first round, she was eliminated by Dinara Safina in the fourth round.

On grass, Sharapova was unsuccessful in her attempt to win in Birmingham for the third consecutive year, losing in the semifinals to Jamea Jackson. Despite that, she was among the title favorites at Wimbledon, where the eventual champion Mauresmo ended up beating her in the semifinals.

Sharapova claimed her second title of the year at the Tier I Acura Classic, defeating Clijsters for the first time in the final.

As the third seed at the US Open, Sharapova defeated top seed Mauresmo for the first time in the semifinals, and then followed up by beating second seed Justine Henin to win her second Grand Slam singles title.

That autumn, Sharapova won titles in back-to-back weeks at the Zurich Open and the Generali Ladies Linz. By winning all three of her round-robin matches at the WTA Tour Championships, she extended her win streak to 19 matches, before it was snapped in the semifinals by eventual champion Henin.

Sharapova would have finished the season as world no. 1 had she won the event. As it was, she finished ranked world no. 2, her best year-end finish yet.