Most Muppets are left-handed. This is particularly noticible in the Muppet musicians such as Floyd Pepper and Janice. Muppet guitarists tend to play with the neck on their right, rather than the normal left. They finger the frets with their right hands and strum with their left hands.

The reason for this is because most of the Muppeteers are right-handed. Their right hands are in use to move the Muppets' mouths and faces, leaving only their left hands for other movement. Usually, this takes the form of a rod attached to the puppet's left-hand. While both of a real guitarist's hands move, on a Muppet, only one can. It was decided that the strumming hand was more important and that the fretting hand could remain stationary along the relatively short necks. This meant the mobile left hand would be the strumming hand, thus making the Muppets play left-handedly.