Possibly but I wouldn't recommend it. My 32gb flash drive takes over a minute to start playing, a 64 gb took 3 minutes. I'm guessing if it worked a 250gb hard drive would be a while before. I also don't know if the usb input on your head unit puts enough power out to run an external drive.
You can although without enough power, you will get playback issues like those mentioned above. There may be some cigarette lighter solutions out there. Also, only use Solid State externals not those SATA ones as they don't like bumps.
I just use a couple 32gb flash drives myself. I have an old 250gb external I'm going to try out just to see. Then I'll take it off roading to see how long it lasts. For power I got myself an 1800w inverter in the jeep so good to go on that part.