In 1546, once the Guatemalan archdiocese was established, bishop Francisco Marroquín split the ecclesiastical duties in the region among the Order of Preachers, Franciscans and Mercedarians, being the latter appointed to take care of "El Barrio" (in present-day San Marcos and Huehuetenango Departments), which was then a part of the Province of Quetzaltenango].

In 1690, the Tejutla "curato" had a large area and included the modern municipalities of Comitancillo, Ixchiguán, Concepción Tutuapa, Sipacapa, Sibinal, Tajumulco, Tacaná and part of what is now San Miguel Ixtahuacán.

According to the historical writings from Recordación Florida of Francisco Antonio de Fuentes y Guzmán, Tejutla belonged to Quetzaltenango Department and it was a "prosperous land with rich weathers and comfortable forest with enough water".

After being annexed by the First Mexican Empire in 1821, the Federal Republic of Central America was founded in 1823, which included the present day San Marcos region of Guatemala.

[6] Towards the end of the 20th century, San Marcos became a hot spot for drug trafficking in Central America, and one of the top lords was Juan Chamalé Ortiz, who was heavily involved in cocaine trafficking, and was accused by US authorities of helping to move over 40 tons of cocaine through Central America en route to the United States.

He owned at least ten estates in his area of operations, including a large farm in Malacatán and provided numerous jobs, in addition to cultivating local support by throwing parties and sponsoring beauty contests.

[7] San Marcos is one of the most important regions in Guatemala given its proximity to the highlands, Mexico, and to the Pacific Ocean coast, where most of the drugs coming from South America land.

He is thought to have worked out a deal that made him the Sinaloa Cartel's top transporter, helping the Mexican group move drugs that arrived via Pacific routes.

[12] Agricultural products include apples, bananas, barley, beans, cacao, coffee, maize, oats, peaches, plantains, potatoes, rice, sugarcane and wheat.

[12] The department produces wooden furniture, with production being concentrated in the Pacific lowlands due to the greater variety of wood available, including cedar, ceiba and tepemixte.