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The defender has been a first-team regular at St James' Park since his arrival in August 2011, but a knee injury has limited his opportunities this term.
Santon did feature in Newcastle's defeat to Leicester City in the FA Cup third round early in January, but has been an unused substitute in the subsequent league matches.
"Life is strange," he wrote on his official Facebook page. "I never expected to return [to Inter].
"Thanks Newcastle and thanks to all the fans for these three and a half years together, we've spent many good times. This city and this team will always remain in my heart.
"I start a new adventure, I'm happy to return to Inter. I started my career there and lived so many important moments, I will give my best to repay the faith."
Neither club has confirmed the details of the 24-year-old's move, but should he return to San Siro he will join a side struggling for form.
Roberto Mancini's side sit 13th in Serie A, having suffered a 3-1 loss to Sassuolo on Sunday.
