Victoria University has warned staff it needs to cut up to 260 positions due to falling enrolments.
At a briefing vice-chancellor Nic Smith said the university was proposing cutting 100-110 academic jobs and 100-150 general staff.
Union members have vowed to fight the plan and said members will not go quietly.
A statement from the university said it had forecast a deficit of $33 million this year.
"This financial challenge has been developing for some years but has been exacerbated this year by a drop in enrolment of 12 percent. This drop is due to the intersection of changes in student demand, demographic changes, low unemployment, and the rising cost of living," it said.
"In order to return to financial sustainability, the university is carrying out an intensive programme of work aimed at increasing enrolment rates and increasing revenue from other sources. At the same time, the university is investigating a range of cost-saving measures across all its operations, both academic and non-academic.
"It has also been necessary to review the sustainability of academic programme offerings and review staffing levels in non-academic areas. Findings from this programme of work are being discussed with staff at forums on 24 and 25 May."
The university said it was an extremely challenging time and it acknowledged the impact on people's lives and careers.
"The university is committed to working through this process as quickly as possible and minimising uncertainty for staff."
Smith said there were no easy options for the university and returning to financial sustainability is a major task.
"But I want to emphasise that my confidence in this University is strong. We have outstanding people and significant opportunities in front of us. All of us are determined that this university will adapt and thrive in the future," he said.
The university last year recorded a $25 million deficit after enrolments fell 8 percent.
Workloads already unmanageable - union
Tertiary Education Union branch president Dougal McNeill said its members did not accept such big cuts were the answer.
"If they go ahead, the result will be unhappy students who will lose their lecturers and supervisors while the standard of service they get from libraries and administrators will reduce. Remaining staff will struggle with further increases to workloads that are already unmanageable," he said.
"We will campaign hard to stop these cuts. University management, government ministers and MPs should be on notice that our members are not about to go quietly."
The government's Budget last week increased tertiary subsidies by five percent from next year and the union said it was disappointed the increase had no impact on the university's plans.
The union's national secretary Irena Brorens said the university and the government should think very carefully about the implications of the cuts.
"We have seen time and time again, the impact widespread cuts like these have on the morale of staff and students and the services the institution exists to provide. Unfortunately, this sort of short-term thinking does not turn a struggling entity around - it's more likely to do the reverse," she said.