The number of people applying for UK university places has fallen by more than 25,000 (4%) on last year, data from the admissions service Ucas shows.
The figures show a sharp decline in those applying to study nursing courses – down 19% – and a continued fall in the number of mature students, notably in England and Northern Ireland.
The number of EU students planning to study in the UK has fallen by 5%.
It is the first decline since fees were last increased in England, in 2012.
Fees in England will increase to £9,250 this year, and student loans are subject to an increase in interest rates – rising from 4.6% to 6.1% from this autumn.
University leaders said a number of factors could be fuelling the fall in applicants, including Brexit, higher fees and funding changes for trainee nurses and midwives.
From 1 August, new nursing, midwifery and most allied health students will no longer receive NHS bursaries – instead, they will have access to the same student loans system as other students.
The latest Ucas figures show the number of people who had applied to UK universities for the coming academic year by the 30 June deadline was 649,700 – compared with 674,890 in 2016.
There have been reductions in applicants from all four countries in the UK. There were:
- 437,860 applications from students in England – down 5% from 459,430 last year
- 48,940 from Scotland – down 1% from 49,470
- 22,530 from Wales – down 5% from 23,740
- 20,290 from Northern Ireland – down 4% from 21,110
Applications from EU students fell from 51,850 in 2016 to 49,250 this year.
However, applicants from overseas countries outside of the European Union are up 2%, from 69,300 in 2016 to 70,830 this year.
There has been a significant drop in mature students (those aged 25 and over) in England and Northern Ireland – down 18% (11,190) and 13% (220) respectively.
Dr Mark Corver, Ucas director of analysis and research, said: "Within the figures, there are contrasting trends.
"How these trends translate into students at university and colleges will become clear over the next six weeks, as applicants get their results and secure their places and new applicants apply direct to Ucas's clearing process."
Prof Les Ebdon, director of Fair Access to Higher Education, said: "The downward trend in mature student numbers is now one of the most pressing issues in fair access to higher education.
"Undoubtedly, the reasons behind the fall are complex and multiple, but universities and colleges should look to do what they can to reverse the decline in mature student applications, as a matter of urgency."
Dame Julia Goodfellow, president of Universities UK, said universities recognised that there were a number of issues to address.
"Continuing to communicate to European applicants that they are welcome and enrich our education system is important," she said.
"The decline in part-time and mature student entrants must also be addressed.
"We recognise also the concern about the total cost of going to university.
"Any analysis needs to cover the cost of maintenance and the interest rate on the loans."
Sarah Stevens, head of policy at the Russell Group, said it would be a concern if EU students were being put off by the uncertainties of Brexit.
"It's positive that applications from overseas students outside the EU have risen slightly," he said.
"International students bring social and cultural diversity to our campuses and this benefits all students, and they contribute £25.8bn to the UK economy."
The Department for Education pointed out that the number of 18-year-olds applying for university was at record levels despite the fall in the overall number of applicants.
A spokeswoman said: "Higher education reforms will give people more choice and universities will be expected to continue improving access and participation in higher education.
"The government is committed to supporting all young people to reach their full potential – whether that is going to university, starting an apprenticeship or taking up a technical qualification."
Pam Tatlow, chief executive of MillionPlus, said the application data from Ucas was "not good news".
"As predicted, the abolition of bursaries has depressed rather than increased applications for nursing and there will be no additional nurses trained in spite of ministers' assurances," she said.
"There is no doubt that the government's approach to Brexit is damaging and is creating huge uncertainties, both for EU students and UK universities."