Another possible context I can think where you might say this is you come across someone who you expected to be sleeping (how come you're not sleeping?) What are you doing up?

This is the second question we've had today about the phrasal verb 'do up'. 'Do up' has two main meanings - to renovate something, particularly a house, or to fasten a garment. So, if your friend's job or hobby is building and decorating, you might say 'What are you doing up?' to mean 'What building are you renovating and modernising at the moment?'. The answer might be 'An old cottage by the sea'. Or if you can hear the sound of a zip (zip fastener/zipper) closing, but can't see what your friend is doing , you might say 'What are you doing up?', and the answer might be 'My jacket'. If neither of those scenarios is relevant, you may have got this sentence wrong. I wonder if you are mixing 'What have you been doing?' and 'What have you been up to?'. Both are common questions to ask someone whom you haven't seen for a long time. (Edit) PS I've just seen Mr Z's answer and Denée's comment. As they've pointed out, the word 'up' can mean 'out of bed'. So if you see someone who should be in bed - such as a child in the middle of the night, or a sick person who should be resting - you might say 'What are you doing up?' to mean 'Why aren't you in bed?'. Very clever. I hadn't thought of that one!

I don't think English speakers say this. We say - "What are you doing?" and "What is up?"

Hi Jay, "What are you doing up?" means "Why are you out of bed and not asleep?" This question is usually asked in the middle of the night (or whenever it's expected that someone is sleeping) to someone who is walking around instead of sleeping. I hope this helps answer your question. Please let me know if it doesn't.