Investigators say the cartel is attempting to gain control of drug distribution channels in several Alberta communities, including Edmonton, Red Deer, Fort McMurray, Drayton Valley and Lloydminster.
Jose Antonio Monterrey, who police allege is the president of La Familia, was arrested earlier this week while trying to board a flight from the Edmonton International Airport.
Cody Sterling Tremblett, 28, Peter Alan Griffon, 34, and Penny Sue Fleming, 34, were also arrested.
In total, 40 drug-related drugs and weapons charges have been laid.
Police say the charges follow searches at three Edmonton homes that uncovered a wide range of weapons, cash, drugs and body armour.
Officers says they seized around $600,000 worth of drugs including five kilograms of cocaine and Oxycodone pills.
La Familia is allegedly connected to an El Salvador gang called Mara Salvatrucha, also known as MS-13.