Northampton Technical College was opened at St George's Avenue—now the site of the Avenue Campus—in 1924. Eight years later, a new building for the College was formally opened by the Duke and Duchess of York. A School of Art opened later in 1937.

At the beginning of the 1970s, Northamptonshire was one of the few counties in England to lack a teacher-training college. A college in Liverpool lost its home and was transferred to what is now the Park Campus. The College of Education was opened by the Secretary of State for Education and Science, Margaret Thatcher, in 1972. In 1975, this College amalgamated with the Colleges of Technology and Art to become Nene College of Higher Education, taking its name from the River Nene. In 1978, it integrated the Leathersellers College from London.

In 1993, the college incorporated St. Andrew's School of Occupational Therapy and was granted undergraduate degree awarding powers. In 1997, it took in the Sir Gordon Roberts College of Nursing and Midwifery.

It became University College Northampton in 1999 and gained full university status in 2005. To gain university status it had to convince the Privy Council that a Royal Decree banning the establishment of a university in Northampton, signed by King Henry III in 1265 following the Battle of Lewes, should be repealed. In 2005, the university also received the power to validate its own research degrees, which had formerly been validated by the University of Leicester. In the graduation ceremonies in July 2006, seven students received the first doctoral degrees validated by the University of Northampton.

In January 2010, the School of Applied Sciences was renamed the School of Science and Technology and moved into the newly refurbished Newton Building at Avenue Campus. The Newton Building was officially opened in September 2010 by Princess Anne.