The strike was the latest salvo in a fierce and bloody 7-month battle for Syria's largest city and economic center, a key prize in the civil war.
Rebels have slowly expanded their control over parts of Aleppo since first storming it last summer. The city is now divided between rebel- and regime-controlled zones.
Rebel forces have been trying for weeks to capture the city's international airport and two military airbases nearby, while the government is bringing in reinforcements from areas it still controls further south and regularly bombing rebel areas from the air.
The Britain-based activist group the Syrian Observatory for Human Rights said 19 people were confirmed dead in the attack late Monday night, including six children and three women.
The activist Aleppo Media Center said more than 40 were killed, though it did not provide names or videos of the dead. There was no way to reconcile the differing tolls.
Both groups said the strike appeared to be from a ground-to-ground missile. The Syrian government did not comment.
Activist Mohammed al-Khatib of the AMC said via Skype that the death toll could rise further as residents search the site for more bodies.
"There are still many martyrs under the rubble. ... There are still lots of people missing from the area," he said.
He said the strike appeared to be from a large ground-to-ground missile because of the scale of the destruction and because residents did not report hearing a fighter jet, as they usually do during airstrikes.
Videos posted online showed scores of men searching the destroyed buildings in the poor Jabal Badro neighborhood for the dead and wounded. One man swung a sledgehammer to break through concrete while a bulldozer hauled off rubble. In another video, a man covered in grey dust struggled under pile of concrete.
The videos appeared authentic and corresponded with other Associated Press reporting.
Although President Bashar Assad's forces regularly shell and launch airstrikes on areas held by anti-government rebels, their use of large missiles has been limited.
In December, U.S. and NATO officials confirmed rebel reports that Syrian forces had fired Scud missiles at rebel areas in northern Syria. That was the last confirmed use of such weapons.
Also Wednesday, rebels clashed with government forces near Aleppo's international airport and the Kweiras military airport nearby, the Observatory said. Clashes have halted air traffic to the two airports for weeks, since rebels launched their offensive to try to capture them.
The Observatory also reported government shelling and airstrikes and clashes between government forces and rebels east and south of the capital, Damascus.
The Syrian state news agency said the army had carried out "successful operations against terrorists" in Aleppo, mentioning a number of neighborhoods that did not include Jabal Badro.
Syria refers to rebels seeking to topple Assad as "terrorists" and blames the conflict on an international conspiracy to weaken the country.
The U.N. says some 70,000 have been killed since Syria's uprising against Assad's rule began in March 2011.
The violence has spread humanitarian suffering across much of Syria.
The U.N. warned in a report released Monday that contaminated water and poor hygiene practices in populated areas have led to an increase in waterborne diseases such as Hepatitis A and Typhoid.
The World Health Organization said the health situation on the ground is rapidly deteriorating, with an estimated 2,500 people in the northeastern Deir el-Zour province infected with Typhoid and 14,000 cases of Leishmania, a parasite responsible for an infectious and often debilitating disease, in Hassakeh province.
It also said Hepatitis A has been reported in Aleppo and Idlib and some crowded shelters hosting displaced people in Damascus.
International diplomacy has failed to stop the violence. The U.S. and other Arab and European countries have called on Assad to stand down, while Russia, China and Iran continue to back him. Russia, Syria's largest arms supplies for decades, has said it will continue to fulfill its arms contracts with Assad's regime.
Russia on Tuesday said it had sent two jets carrying humanitarian aid to Syria and are inviting Russians who want to leave the country to take the flights back.
The Emergency Situations Ministry on Tuesday said the two planes had already left Moscow for northwestern port of Latakia, carrying 40 tons of aid, including portable power generators, blankets, canned food and sugar. It says Russians are welcome to fly back on the planes.
In January, Russia flew 77 of its citizens out of Syria on two flights from Beirut. The foreign ministry says it is not planning a large-scale evacuation.
On Monday, U.N. investigators called on the Security Council to refer Syria to the International Criminal Court, after issuing a report that accused elements on both sides of committing atrocities.
The 131-page report by the U.N.-appointed Commission of Inquiry on Syria detailed deepening radicalization by both sides, who increasingly see the war in sectarian terms and rely on brutal tactics to advance their cause, spreading fear and hardship among civilians.
The report accused both sides of atrocities, but said those committed by rebel fighters have not reached the "intensity and scale" of the government's violations.
The report also accused both sides of using child soldiers, citing the presence of fighters younger than 18 on the government side and under 15 among the rebels.
The commission said it will submit a new, confidential list of Syrians suspected of committing crimes against humanity to the U.N. high commissioner for human rights, Navi Pillay, next month.
Associated Press writers Frank Jordan in Berlin and Nataliya Vasilyeva in Moscow contributed reporting.