The earthquake, with a preliminary magnitude of 6.9, rocked the mountainous region of Badakhshan in northern Afghanistan, triggering landslides and burying entire villages.
The U.N. office in neighboring Pakistan said initial reports indicate between 2,000 and 3,000 people were killed, 2,000 people were injured, 30 villages were affected, and more than 4,100 homes destroyed.
The hardest hit area is around Shari Basurkh, a village that borders Afghanistan's two northern provinces of Badakhshan and Takhar, said Sarah Russell, a U.N. spokeswoman in Pakistan.
Helge Kvam, spokesman for the Red Cross in Geneva, said organization officials in neighboring Tajikistan were told by the Afghan ambassador that 5,000 people were killed. The Red Cross said it was not able to confirm the figure.
According to the report, the dead included 3,000 killed in Shari Basurkh, almost 1,900 killed in a settlement on the outskirts of Faisabad, 140 children killed in a school in Rostaq, and 124 killed in Chaib.
Kvam said the Afghanistan Red Crescent Society, which has offices throughout the earthquake region, has reported it has been able to confirm at least 1,500 dead.
The Deputy Foreign Minister of Afghanistan's government-in-exile Abdullah Abdullah, who is in London, told BBC Radio 5 Live, that the earthquake killed over 5,000 people and he feared the death toll could rise.
From the area, a spokesman for the anti-Taliban alliance, Shamshul Haq Arianfar, said: "We need help desperately. Thousands of people are dead."
He said at least eight villages were completely gone. Speaking from Chaib, on Afghanistan's border with Tajikistan, he said opposition soldiers recovered 1,650 bodies from the rubble.
"We have to tell the people to leave the area," he said. "It is too dangerous."
International aid workers were trying to reach Badakhshan in northern Afghanistan to try to assess the damage.
An earthquake last February in the same region left at least 2,300 people dead and thousands more homeless. At that time, aid agencies struggled to get relief supplies to the region.
Now, the International Red Cross is trying to reach the area with a portable medical unit used during last February's quake, said Juan Fuertes Guillen, head of the International Red Cross office in northwestern Pakistan.
Both the Red Cross and the United Nations were scrambling on Sunday to get aircraft to the region with medical teams and relief supplies, especially tents and plastic sheeting.
In Kabul, aid workers said the weather in the region was overcast and rainy.
The U.N. disaster relief agency, also in Geneva, said its representatives in the region had reported that 3,000 people may have been buried by debri and landslides caused by the earthquake.
The U.N. office in neighboring Islamabad sent planes to the area and was trying to arrange a helicopter to reach remote communities.
The quake was centered in a mountainous area, 45 miles west of Faisabad, the capital of Badakhshan province, said the U.S. Geological Survey in Golden, Colorado.
Shari Basurkh is 24 miles west of Faisabad and close to the epicenter, according to the anti-Taliban alliance, which controls the region.
"We think maybe 3,000 people were killed in Shari Basurkh," said an alliance spokesman known only as Abdullah.
By Zaheeruddin Abdullah