Natalia studied drama at age eight and at twelve started auditioning for advertisements. During her teens she appeared in more than 30 television commercials for such trademarks as Coca Cola, Pepsi and Johnson & Johnson. At the age of 16 she moved to Argentina to work there and unleash her ambition to be a star. She worked as an MTV VJ and in 1995, she landed a role in the soap opera Dulce Ana. She was then cast in the TV series 90-60-90 modelos (1996) and next in Ricos y famosos (1997) (playing Valeria), which received attention throughout Argentina and abroad. Next, she starred in the Argentinian blockbuster Un Argentino en New York (1998). In 1998, Natalia Oreiro recorded the theme "Paths of the Soul" next to Kennedy Choir and with more than 120 Argentine artists under the direction of Instrumental pianist and conductor Nazareno Andorno. There was irony in this role, because after the movie, Natalia lauched her first album, Natalia Oreiro and the single "Cambio dolor" became the opening theme for her next acting project, the prime time show Muñeca Brava (1998-1999), which was an every-afternoon-smash-hit during its run in Argentina. It was also broadcast in some European countries, as well as the Middle East. Her album was successful in those countries as well. For her performance in Muñeca Brava, Natalia was nominated twice (1998 and 1999) for a Martín Fierro Award as best actress in a leading role. In January 2000, Natalia was named "Celebrity of the Year" by E! Entertainment Television. She became an especially popular star in Russia due to the major success of Muñeca brava in that country and was even invited to star in a Russian telenovela. She is also popular in Israel.

She pursued her musical career with the next album Tu Veneno and presentations in "Gala de la Hispanidad", "Gala de Murcia" (both in Spain) and "Festival de la Calle 8" in Miami. Her most important appearance was in the prestigious Latin television show Sábado Gigante Internacional, hosted by Don Francisco. Natalia's major achievement at this time was her music performance in Chile at the Viña del Mar Festival 2000, for which she was crowned Queen of that event. The album scored a Latin Grammy nomination for Best Pop Female Vocal Album, but lost to Christina Aguilera's Mi Reflejo.

On December 31, 2001, she married boyfriend Ricardo Mollo, in Fernando de Noronha. Mollo is the leader of Argentinian rock band "Divididos".

Her third album, Turmalina, was released in 2002 along with her new telenovela "Kachorra". Since 2005, is a vegetarian. In 2006 she joined as the beautiful female boxer, Esperanza Munoz, in the cast of the smash hit telenovela "Sos mi vida" along with her "Muñeca brava" co-star Facundo Arana Her fourth album was scheduled for release in 2006 but the production of "Sos mi vida" went on for longer than anticipated (until December 2006) due to its success in Argentina. It had been rescheduled for release in the end of 2008. For now the album is still untitled.