The health rating of River Wye has been downgraded by Natural England after a decline in important species.
Conservationists worried by the reclassification say without urgent action the waterway will not recover.
The Wye runs between England and Wales and is home to species such as Atlantic salmon and white-clawed crayfish.
Intensive farming and sewage pollution have caused algal blooms which deprive wildlife of oxygen, say campaigners.
Natural England said the updated status, from “unfavourable recovering” to “unfavourable declining”, was the result of a longstanding deterioration in the Wye and its tributary, the River Lugg.
While assessors found water quality to be stable, salmon, macrophytes and native crayfish had declined, resulting in the river as a whole being reclassified.
Joan Edwards, director of public affairs at The Wildlife Trusts, said the verdict represented a “shocking failure” to protect the Site of Special Scientific Interest.
“Wider research shows that farm pollution is the main cause of its decline – that’s why the authorities must enforce the law wherever the causes of pollution are clear,” she added.
Jamie Audsley, chief executive of Herefordshire Wildlife Trust, said government, farmers and regulators needed a consistent plan to restore the river to a favourable condition.
“The Wye should be a river where salmon and otters thrive and people can safely swim,” he said.
Environment Secretary Thérèse Coffey met farmers, environmental groups and English and Welsh politicians in Hereford on Tuesday to discuss improvement actions.
After a roundtable discussion, she said: “The River Wye is clearly struggling and it is vital that we turn the tide on its decline.
“We do all need to work together at a greater pace and with purpose to actively support our farmers and food producers to produce food sustainably and reduce pollution.”
The government has pledged £1.2m to farmers in the Wye catchment for slurry infrastructure and to expand a scheme that offers advice on reducing pollution.