Five children were killed on October 1 when a supporting wall failed, causing a three-story section of a school in the town of Belyayevka to collapse. Four other people, including three students, were injured.
"The Orenburg Region governor accepted on Tuesday Education Minister Alexander Kovalyov's resignation," the local government's press service said. "The minister quit of his own accord due to the tragedy in the school in the town of Belyayevka."
"As head of the regional education system, he feels responsible for the accident," the statement added.
The head of the Belyayevka District, Viktor Oleshko, announced his resignation on Monday.
A school teacher - the dead girls' form mistress - committed suicide shortly after the tragedy.
Regional authorities said earlier on Tuesday that irregularities in construction and an improper maintenance of the school building had led to the degradation of its supporting structures.
The school's administration was also accused of violating a ban on repairs during term time.