Officials said a group of men raided Qabail Primary School in Kandahar before dawn on Sunday, briefly detaining its guards before setting the buildings on fire.
Hayabullah Rafiqi Othak, Kandahar province's education director, said the assailants tied up two security guards then went into each classroom, making bonfires of books and wooden desks that eventually razed the whole school.
The security guards at the school, where 700 girls and boys had studied, were not hurt, he said.
The insurgents claim that educating girls is against Islam and they even oppose government-funded schools for boys because they teach subjects besides religion.
Suspected Taliban insurgents beheaded the headmaster of another co-educational school in the region last Tuesday.
Builders were to start reconstructing it immediately and Othak said some classes may be able to resume when the current two-month vacation ends in March.
The attack came hours after gunmen had tried to set fire to another school in Kandahar, but its guards had scared away the arsonists, Othak said.
Abdul Hakim Hungar, the deputy provincial police chief, said five suspects have been arrested.
Dozens of schools have been attacked and burnt since US-led forces ousted the Taliban in 2001 for sheltering Osama bin Laden, the leader of al-Qaida.
Most of the attacks have been at night and not caused fatalities.