Cardiff University has confirmed plans to cut 400 full-time jobs amid a funding shortfall.
The cost-cutting proposals could also involve course closures, as well as department mergers, with nursing, music and modern languages among the subjects facing cuts.
The Cardiff University and College Union (UCU) called the measures "cruel and unnecessary" and said it would fight plans for compulsory redundancies.
The university said it would only make compulsory redundancies "if absolutely necessary".
Vice-Chancellor Professor Wendy Larner defended the decision to cut jobs, saying the university would have become "untenable" without drastic reforms.
The job role cuts are only a proposal, she said, but insisted the university needed to "take difficult decisions" due to the declining international student applications and increasing cost pressures.
Prof Larner said the university is not alone in its financial struggles, with most UK universities grappling with the "broken" funding system.
She acknowledged that the news would have been "challenging and difficult" for staff to hear, but added that all students on current degrees at the university would be able to complete their degrees.
Dr Joey Whitfield from Cardiff UCU said they were "absolutely shell shocked" by the "cruel and unnecessary" cuts.
"I've had colleagues in tears. They'll damage our members, our students, the city, and Wales as a whole," he added.
He said union members "are prepared to fight any compulsory redundancies tooth and nail".
A Welsh government spokesperson said they were "very disappointed that nursing courses form part of these proposals" and that it was "working urgently" to ensure the same number of nurses are trained in Wales.
They said they understood "the serious concern" the announcement will cause.
"Universities across the UK are facing a challenging financial period due to a range of factors and we expect all institutions to work with trade unions, staff and students on any proposals," they added.
The Royal College of Nursing said the proposal to shut the school of nursing "has the potential to threaten the pipeline of registered nurses into the largest health board in Wales".
Ruth Jones MP, Chair of the Welsh Affairs Committee, compared the job cuts to a "canary in a coalmine" for the severe financial pressures facing universities across the UK.
"It is not only academics and students who will suffer from these cuts, but the wider community in south Wales," Ms Jones added.
Conservative Senedd member Natasha Asghar MS, said she feared "that these concerns will be repeated across our universities in Wales".
Plaid Cymru's education spokesperson, Cefin Campbell MS said the job losses would have "a devastating impact", damaging Wales' "reputation as a nation of learning".
Madison Hutchinson, Cardiff University Student Union president, said they "want to express our unwavering support with all students, and solidarity to staff who may be impacted".
"We have had a commitment from the university that all impacted students will be communicated with tomorrow," she added.
The subjects and programmes being cut also include ancient history and religion and theology.
The university said the proposals would also include the following subject mergers:
The consultation will run for three months, with final plans for approval expected to be considered by University Council in June 2025.
Lloyd Llewellyn-Jones, 57, professor of ancient history at Cardiff University, said the news was "devastating" and "shocking".
He said "major sections of our teaching" in the College of Humanity would be lost, with his own department being "taught out so it won't exist any longer".
"How on earth are we to continue trying to teach over the next few years, with a sword of Damocles hanging over our heads?" he added.
Kristin Milward, from London, studies criminology and sociology, and said hearing the announcement was "scary".
"My lecturer just now was saying he's not sure about his job security - regardless of not being one of the university courses on the chopping block, it is very scary knowing I could be gone at any moment," she said.
"You don't expect to enrol, pay all this money and have this happen to you," she added.
The 20-year-old said her housemate studies nursing and does not know what she will do afterwards, but they are all worried about their future.
"Cardiff is a really great place to be for uni, I really enjoy it and it would be a shame to have people not be able to stay here anymore," she said.
The university had previously said it had to take action to address a £30m black hole in its budget with the pressure of increased costs and falling international student numbers affecting the whole higher education sector.
An offer of voluntary severance between June and September 2024 was taken up and approved for 155 staff and a second round closed earlier this month.
The Welsh government has said that university tuition fees will rise to £9,535 a year from September 2025, in line with an increase in fees for English universities announced by the UK government.
Cardiff University is the largest in Wales, with 32,725 students in 2023.
It is a member of the Russell group of 24 leading and research-intensive institutions, often considered to be the most elite in the country.
Cardiff University is far from alone - Newcastle University, the University of East Anglia and the University of Kent are just some of the institutions looking at how to deal with their multi-million pound financial deficits.
Almost three quarters of universities could be spending more money than they have coming in next year – with a total deficit of £1.6bn predicted - according to the regulator of higher education in England.
There are many reasons behind the increasing black holes, including the fact that international student numbers are down, partly due changes in visa rules.
Tuition fees increased in England in September and for the last two years in Wales, but this followed years of frozen fees.
Further fee increases remain uncertain, but even if tuition fees continue to rise, there is concern it isn't enough to stop universities falling into their overdrafts.
Additional reporting by Sian Elin Dafydd and Charlie Buckland