A backup catcher most of his career, between 1997 and 2004, Blanco played with the Los Angeles Dodgers (1997), Colorado Rockies (1999), Milwaukee Brewers (2000–2002), Atlanta Braves (2003), and Minnesota Twins (2004). Before the 2005 season, Blanco signed a two-year, US$2.7 million contract with the Chicago Cubs to be their backup catcher. After the 2006 season, Blanco renewed his contract for two years with a mutual option for 2009. After the 2008 season, his option was declined making him a free agent.

In the 2000 season Blanco threw out 59 percent of attempted stealers. That was the highest percentage for a catcher since 1982, when California Angels' Bob Boone posted a 56.4 percent success rate. Throughout his career, he has thrown out more than 40 percent of opposing base stealers.

In the 2006 Caribbean World Series, he had a walkoff hit off the top of the opposing shortstop's head in the championship game to give the Venezuelan team the championship.

Through 2008, Blanco is a career .227 hitter with 52 home runs and 241 RBI in 746 games. His career batting average is lowest among active players with 1000 or more at-bats.

He is a cult favorite among Cub fans, among whom he is often affectionately termed "Hank White" by announcers Len Kasper and Bob Brenly.

On January 21, 2009, Blanco signed a 1-year deal to be a back-up catcher for the San Diego Padres. During the 2009 season, he was a pinch-hitter, late-inning defensive replacement, and a mentor for Padres starting catcher Nick Hundley. On December 3, 2009 Blanco signed a one year, 1.5 million dollar deal with the New York Mets. On May 8, 2010 Henry Blanco hit his first home run as a New York Met, a walk-off to help the Mets defeat the Giants 5–4.

On November 30, 2008, Blanco's brother Carlos was kidnapped and held ransom for 200 million Venezuelan bolívares. Despite Henry negotiating with the kidnappers, on December 1, Carlos' body was found shot to death. Blanco and Marielis Useche (Bautista) have three sons together, Henry Jr., Hernis and Heyner.

1 Tomás Pérez | 2 Carlos Guillén | 9 Edgardo Alfonzo | 12 Marco Scutaro | 13 Omar Vizquel | 15 Víctor Moreno | 19 Ramón Hernández | 20 Juan Rivera | 21 Henry Blanco | 23 Ricardo Palma | 24 Miguel Cabrera | 27 Carlos Hernández | 28 Giovanni Carrara | 29 Jorge Julio | 30 Magglio Ordóñez | 31 Víctor Zambrano | 34 Freddy García | 36 Tony Armas, Jr. | 37 Francisco Rodríguez | 38 Carlos Zambrano | 39 Gustavo Chacín | 41 Víctor Martínez | 45 Kelvim Escobar | 47 Endy Chávez | 51 Robert Pérez | 52 Carlos Silva | 53 Bobby Abreu | 56 Tony Alvarez | 57 Johan Santana | 63 Rafael BetancourtManager Luis Sojo

1 Gerardo Parra | 2 Carlos Guillén | 3 César Izturis | 4 José López | 6 Melvin Mora | 7 Luis Maza | 11 Gregor Blanco | 12 Marco Scutaro | 16 Víctor Moreno | 19 Ramón Hernández | 21 Henry Blanco | 22 Jan Granado | 24 Miguel Cabrera | 30 Magglio Ordóñez | 31 Víctor Zambrano | 39 Yoel Hernández | 40 Armando Galarraga | 43 Ramón Ramirez | 44 Orber Moreno | 47 Endy Chávez | 48 Carlos Vásquez | 51 Max Ramírez | 52 Carlos Silva | 53 Bobby Abreu | 54 Enrique González | 59 Félix Hernández | 63 Iván Blanco | 75 Francisco Rodríguez

Manager 8 Luis Sojo | Coach 41 Andrés Galarraga | Coach 20 Tony Armas | Coach 34 Omar Malavé | Coach 5 Oscar Escobar | Coach 10 Roberto Espinoza | Coach 33 Luis Dorante