President Otto Perez Molina said that 40 people died in the state of San Marcos and eight more were killed in the neighboring state of Quetzaltenango.
The 7.4 magnitude quake was centered beneath the Pacific about 100 miles west-southwest of the capital, Guatemala City.
Ground motion triggered mudslides that blocked major roads and buried some of the victims near the Mexican border.
But most of the damage occurred in the mountain village of San Marcos, 80 miles from the epicenter.
About 30 homes collapsed in the heart of the community and frightened villagers gathered around a wide crack that opened up in a street during the temblor.
Workers in the capital and other cities also rushed into the streets as the shaking hit at 10:35 a.m. local time.
The U.S. Pacific Tsunami Warning Center said a small tsunami had been detected off the Guatemalan coast, but no significant changes in sea level were observed along the coast.
The president of the country, Otto Perez, said the country was on the highest level of alert for strong aftershocks after the initial jolt. He encouraged residents in affected areas to evacuate and avoid tall buildings.