Titanium alloys are usually used as structural parts in forged and subsequent heat treated state. Up to now, there have been rare researches appeared on their shaping or forming by multi-stand tandem hot rolling. In this article, we choose Ti-6Al-4V as experimental material and a simulated research has been carried out in a thermo-mechanical simulator MMS-300 to model its hot-rolling process. The plastic flow behavior for Ti-6Al-4V alloy during hot-working has been determined at various deformation temperatures and deformation rates by considering its hot-rolling in single or two phase region. The deformation mechanisms at elevated temperatures are also analyzed in correlation with its deformation activation energy. This research can provide guidance in designing processing parameters for hot-rolling of Ti-6Al-4V alloy.