William H. Prescott was born in Salem, Massachusetts to William Prescott, Jr. and his wife, née Catherine Greene Hickling. His grandfather William Prescott served as a Colonel during the American Revolutionary War.
Prescott suffered from failing eyesight after a thrown crust of bread was temporarily lodged in his eye, while attending Harvard University.
Much of Prescott's work was based on his researches with unpublished documents in archives in Spain.
W. H. Prescott died of a stroke in Boston, Massachusetts.