The 21-year-old has made 35 first-team appearances for the Rams but his chances have been limited by injury and the form of Richard Keogh, Jake Buxton and Zak Whitbread.
He has now joined Stuart McCall's side until January and the Well manager said: “We are delighted Mark has joined us, he is a player we have tracked for some time now.
“He would have been here much earlier but had a slight ankle knock during pre-season. Now that is clear, we are pleased to have him in the squad.
“Everyone who I’ve spoke to rates him highly and this is a great opportunity for him to stake a claim for a regular first-team start and show just what he is capable of.”
Derby boss Steve McClaren added: “It is important Mark gets out and plays some first-team football and going to Motherwell will allow him to do that.
“He has been incredibly patient waiting in the wings behind our other central defenders and it will benefit him going out and playing matches again.”
O'Brien could make his Motherwell debut against Inverness on Saturday.