The strike hit Khuza'a, an area near the border which lies east of the city, killing two militants from the Ezzedine al-Qassam Brigades, the military wing of Hamas.
The Israeli military, IDF, confirmed the strike in south Gaza as well as an earlier incident near Rafah airport which injured four people.
A statement from the IDF said two terrorist squads had been identified from the Hamas terrorist organisation.
"The IDF will not allow any attempt to harm Israeli civilians and will respond with determination to any attempt to use terror against the citizens of Gaza," said the statement.
The latest wave of Israeli attacks was launched after Hamas militants fired an anti-tank missile at a school bus in southern Israel on Thursay critically wounding a teenager.