Men are not generally sufficiently aware of the distinction between the law of God and his purpose; they are apt to suppose, that as the temper of the sinner is contrary to the one, so the outrages of the sinner are able to defeat the other; than which nothing can be more false.

He fought against the flood of paper money and opposed the issuance of bonds without provision for their amortization. During his two pastorates he wrote three well-known works on theology notably the satire "Ecclesiastical Characteristics" (1753) which opposed the philosophical influence of Francis Hutcheson. Witherspoon became prominent within the Church as an Evangelical opponent of the Moderate Party.

As president of the College of New Jersey (1768–94; now Princeton University) he trained many leaders of the early nation and was the only active clergyman and the only college president to sign the Declaration.