Cardona was born in Popayán, Cauca, Colombia on April 25, 1977. At the age of seven, Cardona's family gave him "Manolo" as a nickname. This would later be used as his name as an actor. When he was 18, he moved to Cali, Colombia, to finish his studies. Manolo studied finances and international relations. Manolo's mother, Nancy Molano, is a Psychologist, merchant and Astrologer. His father, Javier Enrique Cardona, has devoted his life to politics, and was the mayor of Popayán. Cardona has two brothers. The elder, Francisco, is an agent and Engineer, and the younger, Juan José, studied film direction in the University of Catalonia in Barcelona, Spain. One of his greatest passions is playing football (soccer).

Cardona began modeling at a very early age. It was his elder brother who introduced Manuel to a modeling agency; he was then quickly signed on to a contract. At the age of fourteen he shot his first television commercial and began modeling professionally for TV commercials, photography, and including runways for several agencies in Colombia. When Cardona was eighteen, in 1995, he began his acting career on a popular Colombian Television series called Padres e Hijos in which he starred for three years. Then in 1998 he won his first lead role in the television soap opera Carolina Barrantes. A year later he became even more prominent for his role in the successful soap opera ¿Por qué Diablos?, portraying a young man who becomes part of a drug organization so he can avenge his friend's death. Later in 2001 came Amor a Mil, a highly popular soap opera in Colombia. In 2002 he signed an exclusive contract with Telemundo and Argos Comunicación, and a year later in 2003 he starred in his first Mexican soap opera, Ladrón de Corazones. In it he portrayed Gustavo Velazco, a man who returns to his home town in Mexico after ten years to avenge his father's death and clear his name. He was the host of Telemundo's Spanish version of Temptation Island. He is also known for his role as Sebastián on the Mexican telenovela Gitanas. In 2005, the film Rosario Tijeras, Cardona's big-screen debut, was released in Colombia. The film was based on Jorge Franco's book of the same name. Cardona worked opposite Flora Martinez (playing Rosario Tijeras) and Unax Ugalde and was directed by Emilio Maille. The film was nominated for a Goya Award for best foreign film. In 2005 the film had its North American premiere at the American Film Institute Festival, in Hollywood.

In 2005 he starred in the film La mujer de mi hermano opposite Bárbara Mori and Christian Meier which was released in the United States in 2006. In 2006 he finished filming "Madrid-Mexico" with Director Enrique Renteria. Cardona is working, with his brothers, on his two production companies "11-11 and Miramas".

On September 27, 2007 Cardona was awarded the "Latin Pride Award" in the Back Bay Events Center in Boston. The award honors the accomplishments of Hispanics of different areas and is a production of the Latin Pride Magazine. Cardona appeared in the 2008 Disney film Beverly Hills Chihuahua.

In 2008, Cardona was in a series, El Cartel de los Sapos for Caracol TV where he played a drug dealer. The series was filmed in Miami, New York, Colombia, Panamá and Madrid. The series was followed by a film of the same name. The series and film were based on a book written by Andres Lopes alias Florecita, who wrote the book while in prison. The series was screened at the LA Screenings and the series aired in 2008 in Colombia. Caracol TV will air the series of 40 episodes starring Cardona, Karen Martinez, Diego Cadavid and Robinson Diaz. The series debuted on Caracol TV on June 5, 2008 continuing until October 2008. Since it premiered in July 2008, El Cartel was the highest rated show on Colombian television. When it premiered on Telemundo in December 2008, it was the highest rated show in the history of the network.

He produced and directed a short film called Risas Inocentes (Innocent laughter) with his brother Juan. The short premiered in Colombia in 2009 and was produced by his company "11:11 (onceonce) films".

Cardona was in third season of Spain's version of Sin tetas no hay paraiso, which aired on Telecinco. In it, he played a policeman named Martin La Roca. The series premiered in Spain in fall 2010.