Blanco was involved in the drug-related violence known as the Miami Drug War or the Cocaine Cowboy Wars that plagued Miami in the late 1970s and early 1980s. This was a time when cocaine superseded marijuana trafficking. It was the lawless and corrupt atmosphere, primarily created by Blanco's operations, that led to the Gangsters being dubbed the "Cocaine Cowboys" and their violent way of doing Business as the "Miami drug war".

Her second husband was Alberto Bravo. In 1975, Blanco confronted Bravo, who was also her Business partner, in a Bogotá nightclub parking lot about millions of dollars missing from the profits of the cartel they'd built together. The Guardian reports: "Blanco, then 32, pulled out a pistol, Bravo responded by producing an Uzi submachine gun and after a blazing gun battle he and six Bodyguards lay dead. Blanco, who suffered only a minor gunshot wound to the stomach, recovered and soon afterwards moved to Miami, where her body count – and reputation for ruthlessness – continued to climb."

In the late 1980s, her lifestyle caught up to her: "Blanco - bloated and in poor health from decades of debauchery – turned over day-to-day management of her Business to three of her sons, and tried to retire to suburban Irvine, Calif." In June 2002, the 56-year-old was in "frail health and had already had one heart attack while in prison."

Blanco had her youngest son, Michael Corleone Blanco, with her third husband, Darío Sepúlveda. Sepúlveda left her in 1983, returned to Colombia, and kidnapped Michael when he and Blanco disagreed over who would take custody. Blanco paid to have Sepúlveda assassinated in Colombia, and her son returned to her in Miami.

In 1984, Blanco's willingness to use violence against her Miami competitors or anyone else who displeased her, led her rivals to make repeated attempts to assassinate her. In an attempt to escape the hits that were called on her, she fled to California.

On February 20, 1985, she was arrested by DEA agents in her home and held without bail. After her trial, Blanco was sentenced to more than a decade in jail. While in prison, she continued to effectively run her cocaine Business.

By pressuring one of Blanco's lieutenants, the Miami-Dade State Attorney's Office obtained sufficient evidence to indict Blanco for three murders. However, the case collapsed due to technicalities relating to a telephone-sex scandal between the star witness and female Secretaries in the DA's office. In 2004, Blanco was released from prison and deported to Medellin, Colombia. Before her death in 2012, the last sighting of Blanco was in May 2007 at the Bogota Airport.

Blanco features prominently in the documentary films Cocaine Cowboys (2006) and Cocaine Cowboys 2 (2008; also written as Cocaine Cowboys II: Hustlin' With the Godmother).

Rapper Jacki-O released a mixtape entitled Griselda Blanco, La Madrina (2010) as an ode to Blanco's lifestyle and character. Griselda Blanco's son, Michael Blanco, later gave his blessing to promote the mixtape.

Blanco played a significant role in Jon Roberts' book American Desperado (2011).

On the night of September 3, 2012, Blanco died after having been shot twice in the head by a motorcyclist in Medellín, Colombia. She was shot at Cardiso butcher shop on the corner of 29th Street, after having bought $150 worth of meat; the middle-aged gunman climbed off the back of a motorbike outside the shop, entered, pulled out a gun, and shot Blanco twice in the head before calmly walking back to his bike and disappearing into the city. She was 69.

Rapper Lil Kim created alter ego "Kimmy Blanco" as tribute to Blanco; Kim debuted this persona in her 2013 single of the same name.

Blanco is portrayed by Mexican Actress Ana Serradilla in the Spanish-language telenovela La Viuda Negra (2014), an adaptation of the book La patrona de Pablo Escobar de José Guarnizo.

Rapper Tech Nine references Griselda Blanco in a line off the song " Is you the Police". Released on the album "Tech Nine Collabos: Strange Reign 2017". The line is as follows "I am high profile, like Griseldas Dope file, why you think I'm aggy when you spoke trial, I'm ghost now".

Catherine Zeta-Jones filmed Cocaine Godmother, a television biopic on drug lord Griselda Blanco, which premiered in 2018 on Lifetime.

Blanco was openly bisexual. According to The New York Post, "Court records show Blanco was a drug addict who consumed vast quantities of 'bazooka,' a potent form of smokeable, unrefined cocaine," "would force men and women to have sex at gunpoint, and had frequent bisexual orgies." Her "favorite possessions included an emerald and gold MAC 10 machine pistol, Eva Peron’s pearls and a tea set once used by the Queen of England." The report continues: "In court, it was revealed that Blanco killed three former husbands as well as strippers, Business rivals – and innocent bystanders, including a 4-year-old boy."