"No one should be under the illusion that a negotiation with Cuba would be easy, or that [there will be] results at all," the legislators said.
"There may be other areas of opportunity. Only by probing Cuba's proposal is it possible to find out."
Flake and William Delahunt, a Massachusetts Democrat, are leading the delegation.
Both are members of the House of Representatives Committee on Foreign Relations and leading members of the Cuba Working Group, which aims to foster better political, economic and cultural ties.
Jane Harman, a California Democrat, said the visitors were told that Fidel was expected to return to power.
On Saturday, the delegates engaged in a marathon of meetings with senior Cuban officials aimed at easing bilateral tensions.
The US and Cuba do not have full diplomatic relations, and Washington has maintained an economic embargo on the Communist state for decades.
Fidel Castro has not been seen in public since July 26, the day before his surgery, although he has appeared in videotaped visits in his hospital room.
Fidel, 80, temporarily stepped aside on July 31, handing power to his brother and defence minister Raul, 75.
The American delegation met on Friday with Ricardo Alarcon, the president of Cuba's National Assembly and the top official for US affairs.
Among Saturday's round of events was a reception with Felipe Perez Roque, the foreign minister, and meetings with Francisco Soberon, the central bank governor, and Yadira Garcia, the basic industries minister, an influential member of the politburo of Cuba's Communist Party.
The timing for the unprecedented visit came hours after John Negroponte, the US director of national intelligence, said that Fidel Castro was close to death.
Negroponte said: "Everything we see indicates it will not be much longer ... months, not years."
The US politicians arrived on the day that Hugo Chavez, the Venezuelan president, denied reports that Fidel has cancer, saying that he was instead fighting a "great battle" against a "serious" illness.
Source: Al Jazeera and agencies