The University opened for teaching in 1849 as "Queen's College Galway" with 37 professors and 91 students. A year later it became part of the Queen's University of Ireland. The Irish Universities Act, 1908 made this college a constituent college of the new National University of Ireland, and under a new charter the name of the University changed to "University College Galway". It was given special statutory responsibility under the University College Galway Act, 1929 with respect of the use of the Irish language as a working language of the University. It retained the title of University College Galway until the Universities Act, 1997 changed it to the "National University of Ireland, Galway".
Located close to the city centre, it stretches along the River Corrib. The oldest part of the University, the Quadrangle with its Aula Maxima was designed by John Benjamin Keane; it is a replica of Christ Church, one of the colleges at the University of Oxford. The stone from which it is built was supplied locally.
Fine Gael's youth wing took a hold on the university in 1973 during the Liam Cosgrave-led Fine Gael/Labour Coalition government, with Enda Kenny and Madeleine Taylor-Quinn among those behind its establishment there.
More modern parts of the university sprang up in the 1970s and were designed by architects Scott Tallon Walker. The 1990s also saw considerable development, including the conversion of an old munitions factory into a student centre. Under the early 21st-century Presidency of Iognáid G. Ó Muircheartaigh, NUI Galway announced details of plans to make the University a "campus of the future" at a cost of around €400 million. Ó Muircheartaigh's successor James J. Browne continued with that plan. The University launched its Strategic Plan "Vision 2020" (for the period 2015–2020) in 2015. 21st-century developments include a state-of-the-art University Sports Centre (Ionad Spóirt), Áras Moyola, J.E. Cairnes School of Business & Economics, the Alice Perry Engineering Building, the BioSciences Research Building, the Life Course Institute, the Lambe Institute and the O'Donoghue Centre for Drama, Theatre and Performance. A new Human Biology Building completed in summer 2017.
Nelson Mandela made a memorable appearance at the University in 2003. On what was his last visit to Ireland, Mandela condemned U.S. foreign policy and received an honorary doctorate from then NUI Chancellor Garret FitzGerald.
Gender discrimination controversy
In 2014 the Equality Tribunal ruled in favor of Dr Micheline Sheehy Skeffington, granddaughter of the famous Irish feminist couple Hannah Sheehy Skeffington and Francis Sheehy Skeffington, who claimed she had been discriminated against on the grounds of gender during 2009. The university "unreservedly" accepted the decision that the "hiring process was flawed". In 2015 with "widespread concern" among staff, mandatory unconscious bias training was introduced for senior staff, including heads of school and interview boards.
In 2017 Dr Elizabeth Tilley was deemed to have exceeded qualifications for senior lectureship following a Labour Court hearing and promoted. In 2018 a further four female lecturers who had also applied for promotion in 2009 were promoted having settled their cases "amicably".
In 2017 the gender ratio of senior NUIG lecturers is 60:40 in favor of men. The ratio of professorships, the most senior academic grade, is 87:13 in favor of men. In 2018 the university achieved bronze status  in the Athena SWAN  recognizes a commitment to advancing gender equality in higher education and research careers.