He graduated as a valedictorian from the College of New Jersey (now Princeton University) in 1769, and he went on to study theology and philosophy under John Witherspoon, whose daughter he married on June 28, 1775.

In his mid-twenties, working as a missionary in Virginia, Smith persuaded the Hanover Presbytery to found a school east of the Blue Ridge, which he referred to in his advertisement of September 1, 1775, as "an Academy in Prince Edward...distinguished by the Name of HAMPDEN–SIDNEY".

[5] The school, not then named, was always intended to be a college-level institution; later, in the same advertisement, Smith explicitly modeled its curriculum on that of the College of New Jersey.

[6] As the college history indicates on its website, "The first president, at the suggestion of Dr. John Witherspoon, the Scottish president of the College of New Jersey (now Princeton University), chose the name Hampden–Sydney to symbolize devotion to the principles of representative government and full civil and religious freedom which John Hampden (1594–1643) and Algernon Sydney (1622–1683) had outspokenly supported, and for which they had given their lives, in England's two great constitutional crises of the previous century.

Classes at Hampden–Sydney began in temporary wooden structures on November 10, 1775, on the eve of American Independence, moving into its three-story brick building early in 1776.

The Latin text of the "letters patent" conferring the arms is dated July 4, 1976; Mr. Brooke-Little—who, with the Queen's special permission, appeared in full herald's uniform—made the presentation on Yorktown Day, October 19, 1976, at the college.

Patrick Henry, then Governor of Virginia, encouraged the passage of the charter and wrote into it an oath of allegiance to the new republic required of all professors.

Patrick Henry, who did not attend college, and James Madison, a Princeton alumnus, were elected trustees in the founding period before classes began.

Among the early nineteenth-century leaders were John Holt Rice, who founded the seminary, Jonathan P. Cushing, and Reverend James Marsh.

The article highlighted a study showing that of all U.S. colleges and universities, Hampden-Sydney had the highest percentage of living graduates listed in Who's Who.

But for tragic reasons, the most significant concert occurred on October 14, 1967, featuring the superstar duet of Marvin Gaye and Tammi Terrell.

On May 11, 1964, Attorney General Robert F. Kennedy visited Hampden–Sydney College to speak with students,[12] and U.S. Vice President George H. W. Bush is said to have given the 1985 commencement address.

[19] The center and program are named for the late Lieutenant General Samuel V. Wilson, a former Hampden-Sydney president who "combined the savvy of a spymaster with the grit of a hardened combat veteran," according to a 2017 New York Times obituary.

These funds were used to construct the Pauley Science Center which replaced the section of the grounds previously host to Bagby Hall.

A neighboring community lodge overlooks Lake Chalgrove and features indoor and outdoor fireplaces and grilling space.

[25] The Pauley Science Center debuted in the fall semester of 2022, with its dedication on November 11, 2024[23] Under the influence of his mentor and father-in-law Witherspoon,[26] Smith named the college for two English champions of liberty, John Hampden (1594–1643) and Algernon Sydney (1622–1683).

Sydney, who wrote Discourses Concerning Government, was beheaded by order of Charles II following his (unproven) implication in a failed attempt to overthrow the king.

Every student must prepare for and pass the Rhetoric Proficiency Exam, which consists of a three-hour essay that is graded for grammatical correctness and the coherence, quality, and style of the argument.

[47] To Manner Born has been highlighted in the New York Times[48] and on the CBS Late Show with Stephen Colbert,[49] who attended Hampden-Sydney in the 1980s.

The 100-year-old student newspaper, The Hampden-Sydney Tiger, has produced many prominent journalists, including Jonathan Martin of the New York Times, Chris Stirewalt of Fox News, Charles Hurt of the Washington Times, Matthew Karnitschnig, the chief Europe correspondent for Politico and a Pulitzer Prize finalist,[53] and Matthew Phillips of CNN, who was previously an editor for Bloomberg Businessweek and Freakonomics.

[60] Several Hampden–Sydney athletes have gone on to successful coaching careers, including Russell Turner, the head coach of the UC Irvine men's basketball team, and Ryan Odom, who led the #16 seed UMBC Retrievers to a historic upset over #1 seed University of Virginia in the 2018 NCAA men's basketball tournament.