The Syrian Observatory for Human Rights said a "huge blast" struck the air force intelligence headquarters in the west of Syria's second city and was immediately followed by "intense clashes".
Observatory director Rami Abdel Rahman told AFP the assault was launched by Al-Nusra Front, Al-Qaeda's Syrian affiliate, and other Islamist fighters.
He described it as a "major attack on the base".
A witness living in regime-controlled areas of Aleppo city said he heard a "huge boom," followed by sounds of gunfire.
There were no immediate reports of casualties. Abdel Rahman said the militants fired mortar rounds at government forces after the blast, and the loyalists retaliated while regime aircraft pounded rebel positions.
Just over a month ago, Al-Nusra and other rebels launched a similar attack on the same intelligence headquarters, first detonating a tunnel explosion and then battling with regime forces.