Cruz has a younger brother, Eduardo, a singer, and a younger sister, Mónica, who closely resembles her: a similarity exploited for some Spanish TV ads. In the 2000s, Mónica left her dancing career and achieved note on her own in the youth-oriented TV series Un Paso Adelante.

Cruz claims to be a vegetarian since 2000, though this fact is disputed. She speaks four languages: Spanish, Italian, French and English. Cruz has also donated a considerable amount of money and time to charity. In 1997 she volunteered in Uganda for two months.

After appearing in the 2001 film Vanilla Sky with Tom Cruise, they had a three-year relationship which ended in January 2004. After filming Sahara in February 2005, she began dating actor Matthew McConaughey. In May 2006, they released a joint statement to People, saying that they "have decided to take time off as a couple." Later that year they announced that they were "no longer intimate and separating was the best thing to do at this time