The £2.5bn shortfall estimate, equivalent to two fifths of the current NHS Wales budget, would be realised if NHS funding rises in line with inflation and the health service maintains annual efficiency savings of 3.7% in real terms after 2015/16, research by the Nuffield Trust found.
However, if spending was increased at the same rate as projected UK national income, the funding gap could be reduced to £1.1bn.
If funding is kept flat in cash terms, the gap could swell to £3.6bn.
The report identified two main drivers of resource pressure in non-acute services: community prescribing, which rose by 4% a year between 2002 and 2010; and GP consultations.
The researchers found appointments for over 16s rose from 12.8 million to 14.0 million between 2002 and 2010, driven mostly by population increase and ageing, rather than increased appointments per person, which was flat.
On current trends, with predicted population growth, by 2025/26 there will be 16.5 million GP appointments plus 11.7 million with a practice nurse for over 16s.
The report explained that NHS funding in Wales fell in real terms in both 2011/12 and 2012/13, and following an increase in 2013/14, is budgeted to continue to fall in real terms until 2015/16.
As a result the NHS budget will be 3.6% lower next year than in 2010/11.
The researchers suggested an increase in investment in primary care could reduce overall costs by reducing activity in the relatively more expensive acute sector.
Lead author and Nuffield Trust senior analyst Adam Roberts said: ‘Our models show that, on the central scenario - maintaining NHS funding level in real terms from 2015/16 - the NHS in Wales is looking at a shortfall worth over two fifths of its annual budget by 2025/26.'
Chief executive at the Nuffield Trust Nigel Edwards, added: ‘The Welsh government – like all others across the UK – will have some difficult decisions to make about NHS funding and services immediately after the 2015 general election.'
Welsh health minister Mark Drakeford said: 'This report recognises NHS Wales is facing challenges into the future, including rising costs, increasing demand, an ageing population, and a growth in the number of people experiencing chronic conditions – the same challenges every healthcare system in the world faces in this age of austerity.
'But it also shows NHS Wales has responded to these through a range of measures including improvements in efficiency and productivity, reductions in length of stay in hospital and hospital admissions.'