By "by hand". I assume you mean using some sort of Intuos tablet with various pen and brush tips and some sort of curve-smoothing software so you can trace over the output of GNUplot, yes?
If by curve-smoothing you mean, "creating a new layer in photoshop on top of the original and trying to draw as carefully as possible".
Plus, he obviously only uses a 'pen' style brush.
Unless he's changed his ways, I thought xkcd was still drawn by pencil and paper, then outlined with pen, scanned in, then touched up via a paint program?
Indeed. Using a math package seems like cheating, somehow.