It is alleged that he spent a quarter of a century smuggling more than 155 tonnes of cocaine into the United States.
The mammoth trial in a Brooklyn federal court starts on Monday, will cost millions of dollars and is expected to last more than four months.
Years have been spent piecing together evidence against Guzman, 61, who was extradited from Mexico in 2017 after twice escaping prison – first hidden in a laundry cart, then slipping down a tunnel that reached his prison shower.
Guzman has been branded the world‘s biggest drug lord since Colombia‘s Pablo Escobar, who was dubbed “The King of Cocaine” and was one of the wealthiest men in the world until police shot him dead in 1993.
Legal experts say the case against Guzman is water-tight and could see him being sent to a maximum security prison for the rest of his life.
The Sinaloa cartel that Guzman founded in 1989 is still hugely powerful and his co-defendant Ismael “El Mayo” Zambada remains at large.
Jury selection will take place amid tight security conditions reserved only for the most dangerous defendants.
Image: Guzman's trial will take place amid high security and with anonymous jurors
US district court judge Brian Cogan will preside over the process behind closed doors.
The 12 jurors, with six alternates, will remain anonymous and will be escorted by US marshals to and from court every day.
The jury will determine whether Guzman – the father of two whose nickname means “shorty” as he is only 5ft 2ins tall – is guilty or not of 11 trafficking, firearms and money laundering charges.
According to the indictment, the Sinaloa cartel, which Guzman is accused of leading from 1989 to 2014, became “the largest drug trafficking organisation in the world… with thousands of members”.
During Guzman‘s reign, the cartel‘s empire expanded across the globe, stretching from the Americas to Europe and Asia.
It is alleged that from 1989 to 2014, the cartel smuggled at least 340,892 pounds (154,626 kilograms) of cocaine into the US, as well as heroin, methamphetamine and marijuana, raking in $14bn (£11bn).
Guzman‘s wealth from drugs was so great that he was on Forbes magazine‘s list of billionaires but he dropped out in 2013 after spending much of his money on protection.
In a secret meeting with actor Sean Penn which the Hollywood star wrote about in Rolling Stone magazine in 2016, Guzman boasted: “I supply more heroin, methamphetamine, cocaine and marijuana than anybody else in the world. I have a fleet of submarines, airplanes, trucks and boats.”
Guzman was born in 1957 in the Mexican town Badiraguato – where several drugs lords operated.
He was recruited by Guadalajara cartel boss Miguel Angel Felix Gallardo, known as “The Godfather” of Mexico‘s modern drug cartels.
After Felix Gallardo was arrested in 1989, Guzman‘s Sinaloa cartel began its meteoric rise.
Guzman is pleading not guilty but the government has presented a wealth of evidence that includes more than 300,000 pages and at least 117,000 audio recordings.
The trial, which one expert says will cost the US taxpayer more than $50m (£38m), will hear several hundred witnesses testify.
Some of the informants have already been absorbed into the US witness protection programme and given new identities and homes around the country.
Image: The shower where El Chapo escaped through a tunnel in 2015.
Guzman has been held in solitary confinement in New York since Mexico extradited him and he spends 23 hours a day in his cell.
The only visitors he is allowed are his three lawyers and twin seven-year-old daughters – the judge banned his 29-year-old beauty queen wife, Emma Coronel, from visiting.
He has complained that his cell is too small and that he is not in good health.
Arrested for the first time in Guatemala in 1993, Guzman spent more than seven years in a Mexican prison before his first escape in 2001.
He was arrested again by Mexican marines in February 2014 but escaped 14 months later before being re-captured in January 2016.
His story has been the subject of numerous documentaries and a Netflix series.