Serna is known for her starring role in I, the Worst of All (1990) portraying famous Mexican religious scholar Sor Juana. She co-starred with Antonio Banderas in Matador (1986), one of the first films by Pedro Almodóvar, and she appeared in such films as Wild Orchid (1990), Chain of Desire (1992), Nostradamus (1994), The Shooter (1995), The Craft (1996) and Kiss & Tell (1997).

Serna was born in Barcelona, Spain. She studied law until she was 19, after which she "preferred being an anarchist" and joined the Barcelona's School of Dramatic Arts. In 1993, she married her co-star in Sharpe's Company, Scott Cleverdon, who portrayed Lieutenant Harry Price in the film.

Serna has written two books on acting technique: Screen acting or El trabajo del actor de cine (1999), which was the first book to be written in Spanish regarding the craft of film-acting, and Monologues in V.O. (2001), a resource for auditioning actors.

They formed Fundación First Team and, since 2000, have taught 4,000 students in 6 countries in collaboration with various film schools and film festivals. The last workshop was at the Guadalajara International Film Festival in Mexico. Foundation First Team always include disabled and under-privileged people in their courses.

She has volunteered in many organizations, such as the Academy of Motion Picture Arts and Sciences (AMPAS), where for four years she helped select foreign movies for the Oscars. She was a board member of the European Film Academy (EFA) for eight years, and raised 1.8 million euros to bring the European film awards to Catalunya in 2004.

On the small screen, Serna is known for playing a Spanish guerrilla in the first four of ITV's Sharpe series of television films based on the novels of Bernard Cornwell, an Italian role in Falcon Crest, and portraying Catherine of Aragon in Henry VIII opposite Helena Bonham Carter and Ray Winstone. She also acted on the popular Spanish TV series Aquí no hay quien viva. From 2011 to 2014, Serna played one of the female leads, Vannozza dei Cattanei, mistress of Cardinal Rodrigo Borgia, in Tom Fontana's historical drama Borgia.

Serna served as President of AISGE (Actores e Intérpretes – Sociedad de Gestión de España), Spain's society of managing intellectual property rights for actors.

She co-produced with Wildcard UK a documentary called Fresco Fiasco and acted in the movie Behold the Monkey, two films about the famous restoration of the Ecce Homo which attracted more than 200,000 visitors from 170 countries to the little town of Borja to see the painting. Both projects were seen in February 2016 on the Sky Arts network in the UK.