After touching down at Cairo airport, Mattis set off to meet President Abdel Fattah al-Sisi, who was hailed by Trump during a White House visit earlier this month.
Sisi's visit marked a shift in relations after Trump's predecessor Barack Obama had given the Egyptian leader the cold shoulder for staging the military overthrow of Islamist president Mohamed Morsi in 2013.
Obama temporarily suspended military aid to Egypt following a bloody crackdown on Morsi's supporters.
Trump, however, has set aside criticism of Sisi's human rights record while pledging to maintain support for the key US ally which receives an annual $1.3bn in military aid.
After meeting Sisi, Mattis is scheduled to hold talks with Defence Minister Sedki Sobhi. He leaves on Thursday afternoon to Israel.
No announcement is expected during the Egyptian leg of the tour, which started with a visit to Saudi Arabia.
In Egypt, talks are likely to touch on the military's counterinsurgency in the Sinai Peninsula, where an Islamic State group affiliate has killed hundreds of soldiers and policemen.
The Pentagon is also concerned with preventing jihadists from crossing Libya's porous border with Egypt and the reported presence of Russian troops in Egypt's western desert, which Cairo has denied.