Prescott enrolled at Harvard College as a sophomore in August 1811, living in the same room where both his father stayed and his future son would stay. Prescott suffered from failing eyesight after a thrown crust of bread was temporarily lodged in his eye. It was a problem that would haunt him for the rest of his life, losing eyesight in one eye completely and in the other significantly, with the remaining eye suffering ups and downs, sometimes being inactive altogether for periods of time. This He graduated from Harvard in 1814. He made an extended tour in Europe, and on his return to America he married, and abandoning the idea of a legal career, resolved to devote himself to literature. After ten years of study, he published in 1837 his History of Ferdinand and Isabella, which at once gained for him a high place among historians. It was followed in 1843 by the History of the Conquest of Mexico, and in 1847 by the Conquest of Peru. His last work was the History of Philip II, of which the third volume appeared in 1858, and which was left unfinished. In that year he had an apoplectic shock, and another in 1859 was the cause of his death.
In all his works he displayed great research, impartiality, and an admirable narrative power. The great disadvantage at which, owing to his very imperfect vision, he worked, makes the first of these qualities specially remarkable, for his authorities in a foreign tongue were read to him, while he had to write on a frame for the blind. Prescott was a man of amiable and benevolent character, and enjoyed the friendship of many of the most distinguished men in Europe as well as in America.
Much of Prescott's work was based on his researches with unpublished documents in archives in Spain.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.
Prescott's History of the Conquest of Mexico was a seminal influence on Edward E. Ayer (1841–1927), a wealthy antiquarian and collector of books and original manuscripts from Native American and colonial-era histories and ethnography. During his lifetime Ayer amassed a collection of more than fifty thousand volumes and documents on pre-and post-Columbian American histories, which as the Ayer Collection donated to the Newberry Library in Chicago represented one of the most extensive and significant Americana collections then accumulated. Ayer credited Prescott's Conquest books as the inspiration behind his efforts and interest in Americanist literature, since as Ayer himself noted they had been the "first books [he] had ever bought and that they had given [him] the incentive to read and taught [him] how interesting history was. In his later memoirs, Ayer confirmed:
I feel that that day, taking those books home, was, perhaps, the happiest day of my life up to that time; and going home I only touched the earth in high places. And I want to reiterate that the finding of Prescott’s Conquest of Mexico in that mine in Arizona in ’62, has been responsible and is to be credited as the principal force that has given me a vast amount of enjoyment in this world, and is absolutely responsible for the “Ayer Collection” in the Newberry Library, Chicago.In 1966 the Colegio Anglo Americano Prescott (school) was founded in Arequipa, Peru in Prescott's honor. The first principal was Manuel Paz Bishop.