The game I am currently creating has a mix of 3D sprites for the inorganic objects and effects, and hand drawn sprites for the organic stuff. It's very much doable and looks good if you know what you want to achieve.
Personally, I wouldn't do it any other way, but if you are new to 3D or are more comfortable with drawing your own 2D sprites, you may not find it's worth the effort.
As far as programs go, I've seen amazing results with Sketchup but prepare spend time learning how to use it. Like anything, you aren't just going to get mind-boggling stuff as soon as you install it.
I haven't touched Blender in a very long time, but I hear it has come a long way since the old cumbersome interface. So that is another option if you go the 3D route.