Blue Cross says it needs to save £1million this year.
The animal welfare charity has confirmed that its rehoming centre in Lewknor will close following 'in-depth consultations'.
14 staff members will be made redundant as a result of the decision.
The charity says it needs to reduce costs in order to continue to help pets that are in need.
Blue Cross has lost almost £10million in the last 18 months, as it hasn't been able to fundraise as normal.
Blue Cross CEO, Chris Burghes said: "It was an incredibly difficult decision to make but it is the best one for the future of our charity and so we can help more pets. Blue Cross will not be leaving the county, Oxfordshire pets will still be helped through our Burford centre, foster care network and through the five other rehabilitation centres we have across the UK.
"Unfortunately, as part of our proposals, despite working to avoid job losses, 14 colleagues, who have been such valued members of the Blue Cross family, will be made redundant. Three team members chose voluntary redundancy, and we are delighted that one colleague has found a new post elsewhere within the charity.
"It is a sad day at Blue Cross to lose some of our wonderful people and they have our heartfelt thanks and our full support at this time.
"We fully understand the strength of feeling shown by some supporters over the proposal to close Lewknor. We stress that throughout the closure period and beyond, all pets which need our services will continue to receive them."
The Blue Cross animal centre in Burford will stay open.
Mr Burghes added: "The plans in the area are part of a broader, UK-wide strategy to reshape and expand our services, putting Blue Cross on a more secure financial footing as we seek to save £1million this year, and helping us towards our vision that no pet or owner goes without help. These plans have been accelerated by the pandemic, which has not only required us to make significant changes to how we operate, but also the possibilities working in new ways can bring."