"I have decided to make changes to meet new circumstances and challenges we have as a country," said Pena Nieto, whose terms runs until 2018.
It was the first significant cabinet reshuffle since much-maligned attorney general Jesus Murillo Karam quit in February, after the presumed slaughter of 43 college students.
Pena Nieto dispensed with Jose Antonio Meade as foreign minister, moving him to the portfolio of social development. Claudia Ruiz Massieu replaced him, according to AFP.
Another major change concerned Renato Sales, who had served as anti-kidnapping commissioner.
He now takes charge of homeland security in place of Monte Alejandro Rubido.
Rubido paid the price for the fiasco involving gang kingpin Joaquin "El Chapo" Guzman, who escaped a high-security prison in July and is still at large.