A son of the Reverend Edward Holyoke, a former President of Harvard, Edward Augustus graduated from that college in 1746. He opened a medical practice in 1748 and practiced for 73 more years, until retiring in 1821. He died in 1829 at the age of 100, surpassing the average life expectancy of the time by fifty years.
Holyoke was also a founder of the American Academy of Arts and Sciences, of which he was president from 1814 to 1820. He was a founder and president of the Massachusetts Medical Society as well, from 1782 to 1784 and from 1786 to 1788. The length of his service to the medical practice and his pioneering work in the advancement of smallpox vaccinations have been acknowledged.