Previous research showed mutations in muscle sarcoplasmic reticulum-bound calcium handler proteins cause swimming defects in embryonic zebrafish. CaMK-II is a highly conserved Ca2+/calmodulin-dependent protein kinase expressed in all vertebrates has been defined to activate and inactivate multiple Ca2+ handler proteins involved in excitation- contraction coupling and relaxation of cardiac and skeletal muscle. In this study, evidence is provided through pharmacological and genetic intervention that CaMK-II inhibition and overexpression causes swimming defects, particularly response to stimuli and swimming ability, reinforced by immunolocalization of skeletal muscle. Transient CaMK-II inactivation does not have any long-term defects to swimming behavior. Overexpression of wild-type, constitutively active, and dominant-negative CaMK-II-GFP in embryos tended to co-localize in fast muscle which led to defects in swimming behavior. This study concludes that inhibition or overexpression of CaMK-II in skeletal muscle diminishes normal swimming behavior specifically in response to mechanical stimulation and swimming ability.