They are accused of using business email fraud schemes and romance scams to con victims - many of them elderly.
Police have so far arrested 14 suspects across the US, 11 in Los Angeles alone.
The authorities say it is one of the "largest cases of its kind in US history".
The FBI investigation is a major step to disrupt criminal networks, US Attorney Nick Hanna said.
"This case is part of our ongoing efforts to protect Americans from fraudulent online schemes and to bring to justice those who prey upon American citizens and businesses," he added.
The FBI started investigating the case in 2016 in a single bank account but it later extended to cover multiple victims in the US and around the world.
All the 80 defendants have been charged with conspiracy to commit fraud, conspiracy to launder money, and aggravated identity theft, the US Attorney's Office in the Central District of California said in a press release.
Many suspects abroad
Two Nigerian nationals, identified as Valentine Iro and Chukwudi Christogunus Igbokwe, who are part of those arrested in the US, have been named as co-conspirators working with others in the US and in Nigeria, to obtain money from victims and then transfer it abroad.
They managed to fraudulently obtain $6m (£5m) in a conspiracy aimed at stealing $46m, the US Attorney's Office alleges.
The remaining 66 defendants are believed to be abroad, "with most them located in Nigeria", the authorities say.
The suspects used illicit money exchangers to move money to Nigeria, generally avoiding transferring the funds directly through banking institutions, the indictment says.
The authorities have listed a total of 252 charges against the 80 suspects.
One of the victims, a Japanese woman named FK in court papers, was conned out of $200,000 after being contacted by a fraudster identifying themselves as US Capt Terry Garcia who wanted to smuggle diamonds out of Syria.
She made 35 to 40 payments, receiving as many as 10 to 15 emails a day directing her to send money to accounts in the US, Turkey and the United Kingdom through the captain's many purported associates, the LA Times reports.