Their protests signaled that the former general, who is also under mounting criticism over the struggling economy, no longer enjoys the broad public support that let him round up thousands of opponents after he seized power in 2013.
In the evening, riot police who had surrounded the site of the biggest demonstration, in the heart of downtown Cairo, dispersed the crowd with tear gas, witnesses said.
Egyptian security forces detained a total of 119 protesters at several demonstrations, according to security officials.
Sisi's government prompted an outcry in Egyptian newspapers and on social media last week when it announced an accord that put the uninhabited Red Sea islands of Tiran and Sanafir in Saudi waters.
"The people want the downfall of the regime!" protesters cried outside the Cairo press syndicate, using the signature chant of the 2011 revolt against then-president Hosni Mubarak, who later stepped down.
They also chanted, "Sisi - Mubarak", "We don't want you, leave," and "We own the land and you are agents who sold our land." In other parts of Cairo, police fired tear gas at protesters, security sources said.
The US government, which sees Cairo as a critical Middle East ally, will continue to watch carefully the situation in Egypt, the White House said.
Saudi and Egyptian officials say the islands belong to the kingdom across the Red Sea and were only under Egyptian control because Riyadh had asked Cairo in 1950 to protect them.
Saudi Arabia and other wealthy Gulf Arab states showered Egypt with billions of dollars in aid and grants after Sisi toppled President Mohamed Mursi of the Muslim Brotherhood in 2013, following mass protests against him.
Egyptians are eager for an economic revival after years of political upheaval. But the islands issue seems to have hurt their national pride, prompting thousands to return to the streets to confront their leader.
There are no signs that Sisi's rule is under immediate threat. However, even local media, which once suggested he could do no wrong, have been attacking the president.
Critics say the government has mishandled a series of crises, from an investigation into the killing of Italian graduate student Giulio Regeni, 28, in Cairo, to a bomb that brought down a Russian airliner in the Sinai Peninsula last October.
Torture marks on Regini's body prompted human rights groups to conclude he died at the hands of security forces, which Egypt denies. That revived complaints of police brutality, one of the issues that led Egyptians to challenge Mubarak's 30-year rule.
Sisi has made fighting corruption a top priority. But he drew fire last month after sacking Hesham Geneina, Egypt's top auditor, who had stirred controversy by publicly concluding that state corruption had cost the country billions of dollars.
In a tweet, Geneina described the protests as the "purest, bravest and most noble demonstration of Egyptians" in decades.
Many Egyptians enthusiastically welcomed Sisi when he took over. They turned a blind eye as Islamists and other opponents were rounded up, swelling the number of political prisoners to about 40,000, according to estimates by human rights groups.
A growing number are now losing patience over corruption, poverty and unemployment, the same issues that led to Mubarak's downfall, while Sisi has appeared increasingly authoritarian in televised speeches.
"We want the downfall of the regime," said Abdelrahman Abdellatif, 29, an air conditioning engineer, at the Cairo protest. "The youth of the revolution are still here ... We are experiencing unprecedented fascism and dictatorship."
There were also Sisi supporters, including a woman wearing a shirt with an image of the former military intelligence chief.
In Alexandria, around 500 people gathered near a railway station. Meanwhile, 300 Sisi supporters holding up photographs of him demonstrated outside a mosque in the port city.
Calls for protests have gathered thousands of supporters on Facebook, including from the outlawed Brotherhood, which accused Sisi of staging a coup when it was ousted and rolling back freedoms won after hundreds of thousands of Egyptians protested five years ago in Cairo's Tahrir Square against Mubarak.