His first approach to acting was after finishing high school when he made a play with some classmates, the comedy Charlatanes by Julio F. Escobar. In the early 1980s he acted in a commercial for Cinzano. He debuted on television in 1980, with Los hnos. Torterolo and then was part of Historia de un trepador. In 1985 he filmed his first film, El telo y la tele, also participated as an extra in the film Los caballeros de la cama redonda starring Alberto Olmedo. He participated in other television series of the 1980s, such as El infiel, playing the role of Felipe for a year. In 1986, he filmed three films, Camarero nocturno en Mar del Plata and Las colegialas. He also acted in television series, such as El lobo and Juegos prohibidos. His career as a television and film actor continued during the following years with films such as Los pilotos más locos del mundo, Paraíso relax and Bañeros II, la playa loca, which had its third part in 2006. His first big hit on television was telecomedy De carne somos, emited by Canal 13 in 1988. After this strip he starred Dalo por hecho, emited by Canal 13 and played an Argentine chanta. In 1989 he participated in one of his greatest successes Los extermineitors, film that parodied the action films of the 1980s. The following year, he filmed the second part of that film, Los extermineitors II. Also in 1992 he played the character Francachella in Brigada Cola where he had a dog called "Tronco". During the early 1990s, he recorded two more parts of the film Los extermineitors, forming a saga that concluded with the fourth part in the southern summer of 1992. He also made two series of great success, La familia Benvenuto and Un hermano es un hermano with Javier Portales. When he returned to work, his fame had grown, even internationally, which is why his next series, Naranja y media it was translated and transmitted in several English countries, with the name of My Better Halves. His next movie, Un Argentino en New York, was filmed in Spain and United States; starring alongside the Uruguayan Natalia Oreiro, it became one of the greatest Argentine cinema hits. In 1999, another challenge would come, the series Trillizos, dijo la partera with the actress Laura Novoa. On this occasion, he had to play three Buenos Aires brothers, Luigi, Marcelo and Enzo, that integrated a classic family of Italian roots, but in turn, each with a different personality that characterized them. In 2000 he filmed Papá es un ídolo it was translated in English with the name of Daddy is My Idol in this movie Manuel Bandera and Millie Stegman. He returned to television in 2001, in one of the most definitive roles of his career, in the comic program Poné a Francella, where he took part in several sketches next to his cast. He had two seasons and aired until December 2002. There he shared the cast with Gabriel Goity, Alberto Fernández de Rosa, Roberto Carnaghi, Florencia Peña, Andrea Frigerio, Mariana Briski, Manuel Wirtz, René Bertrand, Toti Ciliberto and Cecilia Milone and with newly emerged models such as Pamela David, Luciana Salazar and Julieta Prandi. The repetitions were broadcast until 2006 during the weekends in Argentina, while in other countries of Latin America and United States it was televised until the end of 2004. In 2003, he filmed in Cuba, Un día en el paraíso, movie in which Guillermo Francella played two characters, Reynaldo and Roy. That year he starred in the unit comedy, Durmiendo con mi jefe, with Luis Brandoni emited by Canal 13. His next movie, Papá se volvió loco, It was released in 2005 and became a hit in theaters. Since 2005 he worked in the series Casados con Hijos, playing the role of José "Pepe" Argento. For that role, in the first season, Asociación de Periodistas de la Televisión y la Radiofonía Argentinas awarded the Martín Fierro Award to the "Best Leading Actor in Comedy", and in the second season, He was nominated again but lost to Facundo Arana. During these two years, he starred with Enrique Pinti at the Lola Membrives theater in Buenos Aires and then at the Auditorium Mar del Plata the musical comedy The Producers, a great success with both the public and critics. It was Francella's debut in the musical genre. In 2007, he starred in a new comic film, Incorregibles with Dady Brieva and Gisela Van Lacke. It was a success, but received negative reviews. In 2008, he made a special participation in the final chapter of the soap opera Vidas robadas which won the Martín Fierro de Oro Award 2008. At the end of the year, he traveled to Mexico to star Rudo y Cursi along with the Mexican actors Gael García Bernal and Diego Luna. In 2009, he starred alongside Ricardo Darín and Soledad Villamil El secreto de sus ojos which was seen by two million viewers, the most watched of the year. The movie was awarded a Oscar Award for the best non-English speaking film. In 2011, he returned to the small screen with comedy El hombre de tu vida where he played the role of Hugo, a man affected by the midlife crisis. In addition, along with Arturo Puig, he starred in the Ana Katz movie, Los Marziano. In 2012 the film was released ¡Atraco!, which starred alongside Nicolás Cabré and Amaia Salamanca under the direction of Eduard Cortés, personifying a Peronist named Merello. In addition, he had a small role in the film El vagoneta en el mundo del cine. In 2013, he starred in the Marcos Carnevale romantic film, Corazón de León, where he played León Godoy, a short man who falls in love with Ivana Cornejo (Julieta Díaz) a divorced lawyer. For this interpretation he received his second nomination for Silver Condor Award, this time as Best Actor. In 2014, he starred with Inés Estévez and Alejandro Awada the film directed by Daniel Burman, El misterio de la felicidad, where he plays a role of a man looking for his missing friend. In addition, he returned to the theater by Adrián Suar with Dos pícaros sinvergüenzas where he plays Lawrence Williams a man who scams women along with his partner. In 2015, he starred The Clan in the role of Arquímedes Rafael Puccio, together with Peter Lanzani in the role of Alejandro Puccio, based on the murders committed by the Clan Puccio in the early 1980s.