Guy Stevens Callender was born on 9 November 1865 in Hartsgrove, Ohio, the son of Robert Foster Callender and Lois Winslow Callender. The family moved from Massachusetts to the Western Reserve when Callender was a child. At an early age he demonstrated that he had an active mind, intellectual curiosity, and a strong physical constitution; these attributes, along with his being an avid reader of books, led him at the age of fifteen to teach in the district schools of Ashtabula County. Using his savings from several winters of teaching and his summer earnings made working on the family farm, Callender succeeded in paying for college preparatory courses at New Lyme Institute, South New Lyme, Ohio.

In 1886, at the age of twenty-one, Callender enrolled at Oberlin College where he took the classical course. There he was influenced by James Monroe, professor of political science and modern history, who taught courses in political economy and sponsored Callender's volunteer work in the Political Economy Club. Callender also was an active participant in extracurricular organizations, including the Oberlin Glee Club, Oratorical Association, Phi Delta Society, The Review (student newspaper), and the Traveling Men's Association. In these groups, some of Callender's affinity for leadership and exactness became evident (i.e., service as the financial manager and secretary). He graduated with the degree of Bachelor of Arts in June, 1891, counting among his classmates John R. Commons and Robert A. Millikan.

After a year spent traveling and working in the business departments of newspapers in Cincinnati, Indianapolis, and Chicago, enrolled (1892) for graduate study at Harvard University from which he received a B.A. (1893), an M.A. (1894), and a Ph.D. in political science (1897). During his graduate studies at Harvard he served for some time as instructor in economics at Wellesley College, and he was considered an "outstanding man among our graduate students" by Frank W. Taussig and other members of the teaching faculty. Following the award of his Ph.D., Callender held an appointment as instructor in economics at Harvard from 1897 to 1900. There he conducted a course in American economic history, which he personally created. In 1900 he was appointed professor of political economy at Bowdoin College; in 1903 he accepted an appointment as professor in the Sheffield Scientific School of Yale University, where he continued to teach and engage in scholarly research until 1915. He also served as a member of the Governing Board of the Sheffield Scientific School. In 1904 Callender married Harriet Belle Rice; they had one son (Everett, b. 1905).

Callender published his only book, "Selections from the Economic History of the United States, 1765-1860" in 1909. In it he revealed his entire theory of the progress of the United States from the beginning of colonization until the Civil War. Callender's most important contributions are to be found in his condensed, precisely written introductory essays that precede each chapter. His article "The Early Transportation and Banking Enterprises of the States in Relation to the Growth of Corporations," in the Quarterly Journal of Economics (November 1902) was also well recognized and consulted by scholars.

Callender was as a member of the American Historical Association and the American Economic Association, and he was a frequent contributor as a book reviewer, essayist, and speaker. Callender's contribution to scholarship is probably best summed up in his "The Position of American Economic History," American Historical Review 19 (October, 1913). Therein he argued that American economic history should "be pursued as a separate subject of study" and that economic historians must be prepared to interpret facts. For Callender economic history was more than the chronological recital of events of commercial and industrial significance. He sought historical explanations by applying the principles of economic science to the economic and social development of communities. His published studies included an analysis of the part played by economic factors in the adoption of the Federal Constitution and in the debate over the economic basis of slavery in the South.

Prior to his death, Callender worked on several writing projects, including a comprehensive, multivolume economic history of the United States, but poor health prohibited him from completing this project. Another work in progress was a critical essay of Arthur Young's Political Essays Concerning the British Empire (1772), which focused on the history of British colonies in America. Until then, Young’s essays had not been generally appreciated or known by American scholars. Callender was also at work on an introduction for a new edition in two volumes of American Husbandry, which was first published in London in 1775. Callender's review of Cyclopedia of American Government (edited by A.S. McLaughlin and Albert Bushnell Hart) appeared in the Yale Review shortly after his death. According to commentator, Co Wo Mixter, this highly critical review showed "in a marked degree the range, vitality and acuteness of his thinking" (Yale Alumni Weekly, Oct. 1, 1915, p. 48).

Callender was the recipient of numerous awards and honors. In 1907 Yale University awarded him an honorary M.A. Two months before his death the Oberlin College chapter of Phi Beta Kappa elected him to membership. Upon Callender's death from a cerebral hemorrhage in Branford, Connecticut, on 8 August 1915 members of the Oberlin College Class of 1891 purchased from his widow his library of some 2500 volumes and gave it to the institution in his memory. The Class raised additional funds to purchase other titles on economic history, thus rounding out and completing the collection. A small amount of money was also set aside as an ongoing fund to keep the collection up-to-date. Callender's gift to the College Library, established by his graduating class, set an Oberlin precedent.