Blinken meets Egyptian Foreign Minister Sameh Shoukry and heads later on Monday to Jerusalem, where he will hold talks with Israeli Prime Minister Benjamin Netanyahu amid concern at home and abroad over the policies of Netanyahu's new right-wing government.
Blinken will then travel to Ramallah to meet Palestinian Authority President Mahmoud Abbas.
The meeting with Sisi also addressed regional issues including attempts to relaunch a political transition in Sudan and to break the deadlock between rival factions in Libya, according to a statement from US State Department spokesman Ned Price.
After arriving in Cairo on Sunday, Blinken met four activists to discuss the human rights situation in Egypt, said Hossam Bahgat, one of those who took part in the meeting.
Under Sisi, who as army chief led the 2013 ouster of Egypt's first democratically elected president, there has been a long crackdown on political dissent that has swept up liberal critics as well as Islamists.
Rights groups say tens of thousands have been detained. US President Joe Biden's administration has withheld some military aid, citing a failure to meet human rights conditions, though advocacy groups have pushed for more to be held back.
In recent months, Egypt has released some prominent political prisoners amid steps to address international criticism, though many others remain behind bars.
"He was already well aware of the magnitude of Egypt's human rights crisis and that many more new political prisoners are detained than those the regime claims to be pardoning," Bahgat told Reuters after meeting Blinken.
"I think the Biden administration now accepts that two years of engaging Sisi on human rights have not led to much improvement."
US officials did not immediately comment on the meeting with activists.
Sisi has argued that security measures over the past decade were needed to stabilize Egypt and that authorities are protecting rights, including by working to provide basic needs such as housing and jobs.
Reuters