Muhlenberg’s commitment to intellectual and personal growth dates to its founding in 1848. Frederick A. Muhlenberg, who in 1867 became the College's first president, led the College with two purposes in mind: the education of the conscience and the cultivation of the heart. The College’s name honors his great-grandfather, Henry Melchior Muhlenberg, founder of the Lutheran Church in America.

In 1902, the College's Board of Trustees approved the purchase of land in west Allentown, and a year later saw the construction of an administration building (Ettinger Hall) and a residence building (East Hall). By 1920, the Extension School (now known as the Muhlenberg College Wescoe School of Continuing Education), began granting degrees to women. The College would fully open its doors to women as full-time students in 1957.

The 1920s saw the addition of Haas Library (now the Haas College Center) and the Gideon F. Egner Memorial Chapel to campus. By the end of the decade, Trumbower Science building had begun construction. The next 20 years saw substantial growth in both campus buildings and the number of Muhlenberg alumni. By 1948 and 1949, respectively, The Weekly and WMUH both began operation.

In 1951, the first African-American graduates earned Muhlenberg degrees. The following decades saw the construction of Memorial Hall (1954), Prosser Hall (1959), the J. Conrad and Hazel J. Seegers Union (1963) and the Baker Center for the Arts (1976). America's most prestigious honor society, Phi Beta Kappa, welcomed a Muhlenberg chapter in 1967, and the College's inaugurated its first Athletic Hall of Fame class in 1979.

By the late 1980s, the College's needs had outstripped the capacity of Haas Library, and so construction of the Harry C. Trexler Library began. The new building was dedicated in 1988, and two years later the former library was dedicated as the Haas College Center, now home to many of the College's administrative offices.

In 1992, the College joined the Centennial Conference for Intercollegiate Athletics, and in 1997 an anonymous donor provided funds for new athletic fields and academic buildings (Moyer Hall and the Trexler Pavilion for Theatre & Dance).

Muhlenberg became the first liberal arts school to receive Hillel accreditation and foundation status in 1996, and the next year saw the dedication of the New Science Building and the Multicultural Center.

In 2011, the College celebrated the successful completion of The Talents Entrusted in Our Care campaign, finishing with a total of $110.4 million. Capital projects included the renovation and expansion of Seegers Union and the dedication of The Ilene and Robert Wood Dining Commons, the new Hillel House and the Rehearsal House.

In 2015, John I. Williams Jr. was inaugurated as the 12th President of Muhlenberg College, succeeding Peyton "Randy" Helm. Williams led the development of the College's Strategic Plan, instituted a Sustainability Strategic Plan and began building a concerted focus on increased opportunities and outcomes for graduates and the launch of The Muhlenberg Network to facilitate professional connections between students, parents, alumni, faculty and staff.