Several persons were also injured when drones fired at least four missiles at the compound in Buland Khel area of Orakzai Agency, officials were quoted as saying by TV news channels.
Several foreigners were among the dead, the officials said.
A madrassa was being run in the compound by Maulvi Shakirullah, who has links with a Taliban faction led by Hafiz Gul Bahadur, officials and local residents said.
The compound is located in an area close to North and South Waziristan tribal regions.
Five militants were killed when a US drone targeted a vehicle in North Waziristan Agency on Wednesday.
The Pakistan government says the drone strikes violate its sovereignty and are counter-productive.
The foreign ministry lodged a protest with the US embassy on Thursday evening over the drone strikes carried out inside Pakistani territory, the foreign office spokesman Moazzam Khan said in the statement.
"The embassy was informed that drone strikes on Pakistani territory were a clear violation of international law and Pakistan's sovereignty. These attacks were unacceptable to Pakistan," Khan said.
Shakirullah's group is also believed to have links with the Haqqani network and the Al Qaeda.
The Central Investigation Agency-operated spy planes have rarely carried out attacks in Orakzai region since the US launched its drone campaign in Pakistan's tribal belt. This was only the second drone attack in Orakzai Agency. The first was carried out in 2009.