The 20-month operation has led to the arrest of 1,985 people up to now in several U.S. states, including more than 70 this week.
Authorities also seized a total of $62 million in cash, 1,258 kilos (1.38 tons) of methamphetamines, 1,235 kilos (1.36 tons) of cocaine, 456 kilos (1,004 lbs) of heroin, 6,727 kilos (7.4 tons) of marijuana and $3.8 million in assets.
The U.S. deputy attorney general, James Cole, said that with operations like Project Delirium, authorities are able to dismantle Mexican drug cartels on both sides of the border.
"The arrests and seizures we are announcing today have stripped La Familia of its manpower, its deadly product and its profit, and helped make communities large and small safer," Cole said in a statement.
The official repeated the Department of Justice's vow to keep up its "aggressive" efforts, with the aid of its Mexican counterparts, "to diminish and ultimately eliminate the threat posed by these dangerous groups."
Taking part in the operation were some 10 federal agencies that, coordinating with those in Mexico, struck a powerful blow at La Familia, the authorities said.