It said the UK profit fall was driven by the introduction of the 8% bank corporation tax surcharge as well as "the weakening of the pound against the euro following the outcome of the referendum".
The pound has fallen by more than 10% against the single currency since the poll.
Santander also said there was "significant uncertainty about UK economic outlook following the EU referendum and global issues".
The lender added that house price growth in the UK showed signs of slowing while inflation - which is being pushed higher thanks to the fall in the pound - would squeeze real terms income growth.
However, it said some of the risks were mitigated by Bank of England action and the wider strength of the banking sector.
Foreign-owned companies earning sterling revenues are adversely affected by the fall in the pound as it means they translate to lower sums in their home currencies.
Santander said that stripping out tax and currency effects, UK profits were higher, as customer numbers and lending grew.