GPs in England are being given permission to prescribe patients "social" activities, such as dance classes, to tackle loneliness.
The strategy, announced by Prime Minister Theresa May, will also see postal delivery workers checking in on isolated people during their rounds.
The government says about 200,000 older people have not had a conversation with a friend or relative in over a month.
And many GPs see between one and five people a day suffering with loneliness.
As part of the long-term plan, funding will be provided to connect NHS patients in England to a variety of activities, such as cookery classes, walking clubs and art groups, by 2023.
Announcing an extra £1.8m for community projects, such as creating new community cafes, art spaces or gardens, Mrs May said social prescriptions would reduce demand on the NHS and improve patients' quality of life.
The government will also partner with the Royal Mail on a new scheme in Liverpool, New Malden and Whitby to give postal workers a front-line role in tackling loneliness.
And a network of businesses – including Sainsbury's, Transport for London, the Co-op, British Red Cross, National Grid and Civil Service – have pledged to take further action to support their employees' health and social wellbeing.
Launching the first loneliness strategy, Mrs May said: "This strategy is only the beginning of delivering a long and far reaching social change in our country – but it is a vital first step in a national mission to end loneliness in our lifetimes."
She paid tribute to murdered Labour MP Jo Cox, who had campaigned to end loneliness before her death: "Jo Cox was absolutely right to highlight the critical importance of this growing social injustice which sits alongside childhood obesity and mental wellbeing as one of the greatest public health challenges of our time.
"I was pleased to be able to support the Loneliness Commission set up in Jo's name and I am determined to do everything possible to take forward its recommendations."
Kim Leadbeater, Ms Cox's sister, on behalf of the Jo Cox Foundation, said: "The important thing now is to turn the dialogue and strategy into action.
"That is undoubtedly what Jo would want and for every life that is made less lonely as a result of the work she started and that we have all continued, we will take great comfort.
"I look forward to this happening in the coming months and years."