In the first half of the 20th century, Middlesex University was known as a university founded on the principles of equality, freedom, and scholarship, as the school maintained a student population diverse in race, color, and religion, during a time when many universities in the United States had quotas and were not as open. The early foundations of Middlesex University were formed in 1850 when the Worcester Medical College became authorized to grant medical degrees. During the American Civil War, the Worcester Medical College continued as a hospital, but stopped its operations as a medical college. The college remained closed until 1914 when John Hall Smith, a member of the Board of Trustees for the Medical College, led a successful drive to reopen the school. Medical instruction began in 1914 in Cambridge. As the location of the school changed, the school was renamed the Middlesex College of Medicine and Surgery, using Middlesex Hospital in Cambridge. In 1917, the University of Massachusetts was chartered by the state legislature and became affiliated with Middlesex College. The schools had a joint Board of Trustees.
As Middlesex College began to grow, John Hall Smith chose a site in Waltham, what is today the Brandeis campus, to accommodate the college's expansion. The Castle was built in 1928 and was the main building of instruction on campus, containing classrooms, labs, and lecture rooms. In 1935, the Middlesex College of Medicine and Surgery changed its name to the Middlesex College, as the state legislature allowed for the school to confer degrees of Bachelor of Arts and Bachelor of Science. In 1937, the Middlesex College and the University of Massachusetts merged to become Middlesex University. Prior to World War II, Middlesex offered instruction in the schools of medicine, liberal arts, pharmacy, podiatry, and veterinary medicine.
For many years Middlesex University had difficulty gaining accreditation from the American Medical Association (AMA). New legislation passed in 1944 required doctors to have graduated from an AMA-approved university in order to be licensed. According to the AMA, Middlesex, among other problems, lacked the sufficient funds, facilities, and faculty needed to gain accreditation. Controversy surrounded this AMA decision regarding Middlesex, and some at the university accused the AMA of antisemitism. Many Middlesex students and faculty members were Jewish, and the university maintained a racially and religiously diverse community. The lack of AMA accreditation, combined with declining enrollment due to the Second World War, doomed the university. As the war drew to a close, Middlesex found itself in a grave financial situation and faced the prospect of shutting down completely.
The University's situation caught the attention of the Albert Einstein Foundation, which was looking for an opportunity to establish a Jewish-sponsored, non-sectarian school based strictly upon merit and open to the entire world, regardless of race, color, or religion. These ideals mirrored Middlesex's own principles, and the trustees of the troubled school decided to transfer the university's charter and property in 1946. The new institution became Brandeis University, which opened its doors in the fall of 1948.