Impairment in cognition and motor activity are commonly encountered in patients affected by multiple sclerosis (MS), and depression is believed to be a contributing factor. The aim of the present study was to investigate the impact of induced depression on a cuprizone mouse model of demyelination and the effectiveness of enhanced environment (EE) as a method of intervention. C57BL/6 male mice were divided into five groups: Cuprizone only (Cup-O), cuprizone undergoing depression (Cup-Dep), cuprizone housed in EE (Cup-EE), cuprizone housed in EE and undergoing depression (Cup-ED) and the control (n=9–10 per group). Depression was induced by repeated open-space forced swim. Neurobehavioral tests were conducted following a 6-week period of 0.2% cuprizone-enriched diet. The Cup-EE group performed significantly better in terms of cognition and motor functions, when compared with the Cup-O group, as evidenced by the Morris water maze (MWM; P<0.001) and rotarod performance test (P<0.05) results. Conversely, the Cup-Dep group exhibited a significant decline in performance in the MWM (P<0.001) and rotarod performance test (P<0.05), when compared with the Cup-O group. The Cup-ED group had comparable results to those of the Cup-O group, indicating a reversal of the induced depression effects. Open field test results failed to show an anxiety-like behavior in the cuprizone mouse model. It was therefore concluded that EE can improve MS-associated cognitive and motor deficits. Insights gained from these results facilitate the exploration of non-medical modes of intervention as an emerging adjuvant therapy in MS.