Jonathan Dickinson, born in 1688 and graduated from Yale College in 1706, was the first president of the College of New Jersey. After becoming the pastor of the Congregational church in Elizabethtown, New Jersey, Dickinson shifted from Congregational to Presbyterian teachings in order to join the Presbytery of Philadelphia. Yet while becoming a leader within the Presbytery and the higher Synod of Philadelphia, Dickinson steadfastly maintained his belief in the freedom of the individual clergy. Having first envisioned an educational institute within the Synod, Dickinson only realized his dream of founding a school to train future Presbyterian ministers and pious laymen when he and others founded the College of New Jersey in 1746. Dickinson died in office in October 1747.

While Jonathan Dickinson bears the distinction of serving as Princeton University's first president, Aaron Burr played a central part in organizing the College after its initial establishment and overseeing its move to Princeton in 1756. Burr was born in Fairfield, Connecticut in c. 1715/1716 and graduated at the head of his Yale College class in 1735. From there he moved to Newark, New Jersey to head both the Presbyterian church and a school in classics. Burr, along with Dickinson and five others, established the College of New Jersey in 1746. In 1748 Burr was named president of the college, though he had filled this office unofficially since Dickinson's death in 1747. During Burr's ten years of service he increased enrollment, raised much-needed funds, presided over the erection of Nassau Hall, and instructed the first classes of students to graduate from the College of New Jersey.

Jonathan Edwards succeeded his son-in- law, Aaron Burr, Sr., to become the third president of the College of New Jersey in September 1757. Edwards studied theology at Yale College, preached in the Presbyterian Church, and is remembered for his belief that only the truly converted should receive Communion, rather than all baptized persons. However, his proposal along these lines led to his dismissal from the Northampton, Massachusetts Presbyterian church in 1750, after which he passed his days serving as a missionary and writing with a passion. Edwards accepted the office of president with some reluctance but continued to preach actively from the College's pulpit. He died in March 1758 after being inoculated for smallpox, just six months into his tenure. His three sons and eight daughters survived him.

Having declined the presidency of the College of New Jersey in 1758, Samuel Davies accepted it in 1759 with a reluctance akin to that of his predecessor, Jonathan Edwards. Davies, who thought that his successor, Samuel Finley, was the right man for the job, was urged to take the position, even though some of the College's trustees shared his high opinion of Finley. Born in 1724 in Summit Ridge, Delaware and educated both at home and in the Rev. Samuel Blair's seminary, Davies received his license to preach in 1746 in Newcastle, Delaware. Ordained the following year as an evangelist to Virginia, he went on to serve as the first moderator of the Presbytery of Hanover, encompassing all the Presbyterian ministers in Virginia and North Carolina. At the request of the trustees, Davies traveled to Great Britain with Gilbert Tennent in 1753 to raise funds for the College. Among other uses, the donations collected abroad served to fund the construction of Nassau Hall and the president's house. As president and professor at the College of New Jersey, he was renowned for his emphasis on public service.

As president of the College of New Jersey, Samuel Finley is known for increasing enrollment and for his popularity as a teacher. Finley was born in 1715 in Armagh County, Ireland. On immigrating to America in 1734, he immediately began to educate himself with the goal of becoming a minister and was ordained in 1740 in New Brunswick, New Jersey. During his seventeen years as pastor of the church of Nottingham, Maryland, he oversaw its educational academy. Early in his career, Finley preached in a contentious manner, very much in keeping with the spirited religious revivals of the Great Awakening, but he later moderated his tone. He received an honorary degree from the University of Glasgow before becoming the fifth president of the College of New Jersey in June 1761, serving in this role until his death in July 1766.

John Witherspoon arrived in America from Scotland in 1768 having been persuaded by the trustees and then medical student Benjamin Rush to assume the presidency of the College of New Jersey. After declining initially, Witherspoon, a graduate of the University of Edinburgh, became one of the most popular and influential presidents in Princeton University's history. Witherspoon served not only Princeton, but also the nascent United States as a member of the Continental Congress. During Witherspoon's tenure the College weathered the turmoil caused by the American Revolution: Nassau Hall sustained heavy damage, enrollment declined, and finances were precarious. In the wake of this conflict, Witherspoon's preaching tours increased enrollment, particularly from the southern United States, and he broadened the curriculum by his emphasis on English grammar and composition. He also obtained needed instruments of instruction such as books for the library and apparatus for scientific study (such as the Rittenhouse Orrery). Witherspoon advocated a well-rounded clergy, emphasizing the liberal education of students, rather than just religious instruction. It was his aspiration to produce men who would not only make exceptional clerics, but also outstanding statesmen. Witherspoon instructed many students who became notable for their contributions to state and federal government, including James Madison, Aaron Burr, Jr., William Smith Livingston, Andrew Kirkpatrick, and Ashbel Green. Part of Witherspoon's popularity and influence with both students and politicians derived from his ability to discuss the merits of contesting views, while using reason to reach an ultimate conclusion.

Samuel Stanhope Smith, born in 1751 in Lancaster, Pennsylvania, was the first alumnus to become president of the College of New Jersey. His father, Robert Smith, taught him at the school he headed in Pequea, Pennsylvania until the age of sixteen, when Samuel entered the College of New Jersey as a junior. He graduated with honors in 1769 before returning to Pennsylvania to teach in his father's school. In 1771 he returned to Princeton to tutor and study theology under John Witherspoon. For health reasons, he left Princeton to work as a missionary in Virginia. In 1775 the seminary that later became Hampden-Sydney College was founded, and Smith became its president. Married to Ann Witherspoon, Witherspoon's daughter, Smith returned to Princeton in 1779 as a professor of moral philosophy, and his brother, John Blair Smith, replaced him as president of Hampden-Sydney College. On Witherspoon's death in 1794, Smith, who had become vice president in 1786, assumed the leadership of the College. After the Nassau Hall fire of 1802, he raised enough money not only to reconstruct the landmark but also to add two additional buildings. Unfortunately, a riot in 1807 led to the suspension of 125 students and a growing distrust on the part of trustees. Faculty resignations and a declining student body led to Smith's resignation in 1812.