A vote on Saturday evening at its General Assembly backed a motion that will allow gay couples to tie the knot in URC churches.
The first same sex weddings could take place as soon as the Autumn, officials said.
Assembly voted in favour of the resolution by 240 votes to 21 votes. United Reformed churches wishing to register their buildings for the marriage of same-sex couples are now able to start that process immediately.
The decision whether to hold gay marriages will be left to each individual church.
Small churches, like Steve Chalke's Oasis group, have already said they will conduct gay marriages but with 56,000 members in Britain the URC is by far the biggest to change its rules.
The decision comes on the eve of the Church of England's crucial shared conversations on sexuality, although the CofE will not change its positon on the back of the discussions.
Elsewhere Quakers already allow gay marriage and the Scottish Episcopal Church is now widely expected to pass a motion allowing same sex unions next summer.
Critics of gay marriage say it is unbiblical and God is clear that marriage is between one man and one woman.
Revd John Proctor, General Secretary of the URC said: "Today the URC has made an important decision – at which some will rejoice and with which others will be uncomfortable.
"Those of our churches who now wish to offer full marriage services to same-sex couples are free to do just that – and those churches who do not wish to are not compelled to. All are part of this denomination.
"This has been a sensitive issue for many in our churches. It has been important to take our time over the decision process, and to listen as carefully as we can to one another along the way."