Guterres's comments came after he met Egyptian President Abdel Fattah al-Sisi, and a day after a senior White House official said the United States would not insist on a Palestinian state alongside Israel.
"There was a complete agreement" that a resolution needs a "two state-solution and that everything must be done to preserve that possibility," Guterres said.
Later, in a speech at Cairo University, Guterres said the Israeli-Palestinian problem was the "mother" of regional conflicts.
"There is no Plan B than a two-state solution," he added.
A senior Palestinian official denounced the White House comment on Wednesday, saying it was irresponsible.
"This does not make sense," Palestine Liberation Organisation (PLO) executive committee member Hanan Ashrawi told AFP.
"This is not a responsible policy and it does not serve the cause of peace.
"They cannot just say that without an alternative," she added.
The White House official's comments came ahead of talks between US President Donald Trump and Israeli Prime Minister Benjamin Netanyahu later Wednesday in Washington.
"A two-state solution that doesn't bring peace is not a goal that anybody wants to achieve," the official said on condition of anonymity.
For the better part of half a century, successive US governments -- both Republican and Democrat -- have backed a two-state solution.
PLO secretary-general Saeb Erekat said the organisation remained committed to two states and would oppose any system that discriminated against Palestinians.