Players automatically lose whatever cool points come with playing Guitar Hero when using the keyboard and mouse, although a few geek points can be won using a wireless keyboard as a makeshift guitar. However, the keyboard and mouse come with significant benefits. Firstly, players don't have to go out and buy another guitar for multiplayer. Secondly, clicking a mouse is a lot faster than strumming a guitar, which helps a lot during rapid fire sequences. Aspyr mapped the frets to the keys, strumming and Star Power to the mouse buttons and the whammy bar to the mouse, which players must shake to activate. Playing with a keyboard makes the game feel more like a game than a musical experience, and gamers should blow through every song on easy except for Raining Blood, which is ridiculously hard on all controllers and difficulty settings. Things get trickier in Medium difficulty, since the pinky finger doesn't get a great workout in normal settings, and the power cords (when two frets are held at the same time) can be just as hard as doing them on the guitar. But using the guitar provides the best playing experience by making the player feel like a rocker.

Things get trickier when moving to medium or harder difficulties. Some of the guitar sequences don't match the song as well as they should, which sometimes makes the experience feel more like banging on buttons than playing guitar, and leads to weird situations like how certain parts of Barracuda are easier to play in Hard mode than in Medium. The extreme differences between difficulties also makes the guitar battles against famous guitarists like Slash less fun, because not only can the computer pull off its notes perfectly, but it has the benefit of playing the last sequence of notes and then causing something called Death Drain, which can completely crush players even if they have a slightly higher rock meter.