MS criminal activities include drug smuggling and sales, black market gun sales, human trafficking, assassinations for hire, theft, and assaults on law enforcement officials. Their activities have caught the eye of the FBI, who in September 2005 initiated wide-scale raids against suspected gang members, netting 660 arrests across the country. In the United States, the gang's strongholds have historically been in Washington, D.C., Miami, and Southern California.

Former gang member Brenda Paz said that MS is well structured, with multiple leaders, and that the gang's goal was to become the top gang in the United States.

On July 23, 2003, Brenda Paz, a pregnant 17-year old girl, was found murdered on the banks of the Shenandoah River in Virginia. Police believed she was killed to prevent her from cooperating in MS-13 related investigations in six states. Four of her friends were later convicted of the murder.

On December 23, 2004, one of the most widely publicized MS-13 crimes in Central America happened in Chamelecón, Honduras. An intercity bus was intercepted and sprayed with automatic gunfire, killing some 28 passengers. Those convicted were MS gang leaders and in February 2007 the courts found Juan Carlos Miralda Bueso and Darwin Alexis Ramírez guilty of several crimes including murder and attempted murder. Ebert Anibal Rivera was held over the attack and was arrested in Texas after having fled.

While another, also accused of masterminding the attack, Juan Bautista Jimenez, was killed in prison. According to the authorities he was hanged by fellow MS-13 inmates.

On May 13, 2006, Ernesto "Smokey" Miranda was murdered at his home in El Salvador, a few hours after declining to attend a party for a gang member who had just been released from prison. He had begun studying law and working to keep kids out of gangs.