The Brotherhood on Friday declared its candidate Mohammed Mursi the front-runner in the May 23-24 election after all the votes had been counted, with Shafiq in second place.
Several newspaper websites also put Mursi and shafiq out in front after the voting on Wednesday and Thursday.
A run-off between Shafiq and Mursi will further polarise a nation that rose up against the authoritarian Mubarak 15 months ago but has since suffered a spike in violence and a declining economy.
The electoral commission is expected to declare the official results on Tuesday, but tallies of the vote counting provided by the official MENA news agency and Al-Ahram newspaper showed Mursi in first place and Shafiq in second.
"We have complete numbers now. Complete, after adding expatriate votes," said Essam al-Erian, the deputy head of the Brotherhood's political arm.
Erian told a press conference it was "completely clear" that Mursi and Shafiq had topped the presidential vote and would compete in the run-off on June 16-17.
He said Mursi won 25.3% of the vote, and Shafiq 24%. Pan-Arab socialist Hamdeen Sabahi won 22%, Erian said.
Both Mursi and Shafiq had been written off as long shots just weeks before the historic election in which the country freely voted for the first time to elect a president after Mubarak's ouster in a democratic uprising.
Shafiq's success appears to have shaken the influential Islamist movement, which won parliamentary and senate elections held last winter.
"The slogan now is: 'the nation is in danger,'" Erian said. He said Mursi himself was calling losing candidates for a meeting on Saturday to ensure Shafiq would not win the election.
"The revolution is in danger, we need to have a democratic country, Shafiq is against democracy," he told AFP after the press conference.
Another Brotherhood official told AFP that Mursi would personally call the movement's bitter rival Abdel Moneim Abul Fotouh, a former Brotherhood leader who ran independently of the movement.
"We call on all sincere political and national forces to unite to protect the revolution and to achieve the pledges we took before our great nation," a Brotherhood statement said.
"Today we face desperate attempts to reproduce the old regime," it said.
Fotouh's campaign earlier issued a statement calling on Egyptians to confront "the corrupt regime" in the run-offs, in a veiled reference to Shafiq.
A spokesman from Shafiq's campaign, Karim Salem, denied that his candidate would represent a retreat from the goals of the uprising.
"No, (the Mubarak) era is finished, politics have changed. Egypt is entering democracy," Salem said.
In Cairo, voters were thrilled by the free, contested election, whose results were not predetermined, but conceded that many challenges lay ahead.
"It's our first year of democracy, like a baby that is still learning to crawl," said Mustafa Abdo, a bank employee.
The election, which saw 50 million eligible voters given the chance to choose among 12 candidates, was hailed by US Secretary of State Hillary Clinton, who congratulated Egypt on its "historic" presidential election, and said Washington was ready to work with a new government in Cairo.
Electoral commission officials said turnout was around 50% over the two days of voting.
Contenders included former foreign minister and Arab League chief Amr Mussa, who touted his experience but was hammered for his ties to the old regime.
The election seals a tumultuous military-led transition from autocratic rule marked by political upheaval and bloodshed, but which also witnessed parliamentary elections that saw Islamist groups score a crushing victory.
The Supreme Council of the Armed Forces, in power since Mubarak's ouster, has vowed to restore civilian rule by the end of June, after a president is elected, but many fear its withdrawal from politics will be just an illusion.
The army, with its vast and opaque economic power, wants to keep its budget a secret by remaining exempt from parliamentary scrutiny, maintain control of military-related legislation and secure immunity from prosecution.
Mubarak, 84 and ailing, is being held in a military hospital on the outskirts of Cairo where he awaits the verdict of his murder trial on June 2 over the deaths of protesters during the uprising.