It's hard to quantify "most powerful," since none of them ever filed a tax return or issued an annual report describing their work force, main businesses and assets.
Charlie Luciano would make the short list because he formed the Commission in 1931,and in effect, was its chairman. He was also the first "modern" Don (as opposed to a "moustache Pete"). Frank Costello probaby had more political power than any Don in history, and IMO was the model for Vito Corleone. Carlo Gambino's family was the most powerful in America, and took in more money than any other; Don Carlo never went to prison and died peacefully--two major marks of success.
Don Vito Cascio Ferro can be said to be the "Godfather" of the godfathers--he was a powerful Sicilian Don of the early 20th century who forged ties with American Mafia families and had great influence with some of them. But he was not a big power in America.