Federal prosecutor Brian Kelly told jurors Bulger was a "hands-on killer" and the source of "murder and mayhem" in the city, WCVB-TV in Boston reported.
Bulger, 83, who once was one of the FBI's most wanted fugitives, is charged with participating in 19 killings in the 1970s and 1980s as leader of the Winter Hill Gang.
The prosecution plans to call three former Bulger associates who have implicated him in the killings and other crimes. As many as 80 witnesses may testify against Bulger.
The trial is expected to last up to four months.
Bulger's attorney said last August his client planned to testify.
Bulger became a fugitive in 1994 after a crooked FBI agent, John Connolly, told him he was about to be indicted on federal racketeering charges, CNN reported.
He was captured in 2011 in Santa Monica, Calif., living under a false name and pleaded not guilty to the charges at his arraignment.
He also is accused of using violence and threats to shake down Boston loan sharks, bookies and drug dealers.
Bulger has argued he was given immunity by the FBI and a former prosecutor in his role as an informant relaying information about the Italian Mafia to federal authorities.