Vincent Zambaba accepted the charges levelled against him in a case originally filed in Washington DC in 2002 that were then transferred to Chicago in August.
Although Mr Zambada faces 10 years to life imprisonment, according to the Chicago Tribune, he could see his sentence reduced if he continues to give valuable information and testify against Mr Guzman.
Jury selection for Mr Guzman’s trial in New York wrapped up this week, with opening statements set for 13 November.
Mr Guzman, who has been held in solitary confinement, has pleaded not guilty to charges that include smuggling drugs into the US for over 25 years, running a violent drug cartel and escaping Mexican jails twice.
Having worked closely with the 61-year-old drug lord for years, Mr Zambada would know vital information about the Sinaloa Cartel.
Before his 2009 arrest, he oversaw cartel logistics for illegal shipments of drugs bound for Chicago other US cities. The 43-year-old also had authority to order hits, court documents state.
Security has been a concern since his extradition to Chicago in 2010. He wasn’t allowed on a rooftop recreational area at his city jail from fear a sniper could shoot him from an adjacent skyscraper.
Prosecutors said that as part of a plea deal they will recommend the US government provide security to him and his family after acknowledging how dangerous taking the stand would be.
If he does testify, he and his family would be permitted to stay permanently in the United States, the agreement said.
Mr Zambada has agreed to contest the government’s seizure of $1.3bn in ill-gotten assets in a related case.