Media playback is not supported on this device
Diana Taurasi and Lindsay Whalen scored 17 points apiece for USA, gold medallists for the eighth time in 10 appearances.
Victory extended USA's Olympic winning streak to 49, dating back to the bronze-medal match at Barcelona 1992.
Spain's silver was their first Olympic medal of any colour in women's basketball.
The world's third-ranked team had lost 103-63 to the United States in the group stage.
Spain's Alba Torrens scored a game-high 18 points, but USA were comfortable winners, leaving coach Geno Auriemma in tears.
Victory brought a fourth consecutive Olympic gold for Taurasi, captain Sue Bird, and Tamika Catchings.
Earlier, Serbia won bronze by beating France 70-63.
Subscribe to the BBC Sport newsletter to get our pick of news, features and video sent to your inbox.
Find out how to get into basketball with our special guide.
USA won their sixth successive Olympic women's basketball title, beating Spain 101-72 at Carioca Arena.