The frequent use of the computer mouse was reported to be associated with the development of the musculoskeletal disorders in the wrist, forearm, and shoulder regions. This study was to examine the effect of the mouse weights and operation speeds on the wrist motion and muscle activity. 25 subjects (20 males and 5 females) were instructed to repetitively point-and-click the mouse between two targets displaced in the monitor with five different weighted mice (weights around 70, 100, 130, 160, and 190 g) at the fast (50 repetition/min) and slow (25 repetition/min) operation speeds. Surface electromyographic activity of the extensor carpi radialis, extensor carpi ulnaris, extensor digitorum, and upper trapezius muscles were recorded, and the electrogoniometer was used to register the wrist motions. The results showed that the maximal ulnar deviation was not significantly different among the examined conditions. The wrist movement range and the forearm muscle activities showed a V-shape tendency with the lowest value in the mouse weight of 130 g. This tendency was diminished during the slow speed tasks. The results suggested that the proper mouse weight could benefit the users in terms of increasing the movement efficiency and decreasing the muscular costs.