Fatigue and physical deconditioning are common, difficult to treat conditions among patients with systemic lupus erythematosus (SLE). The aim of this pilot study was to evaluate the effectiveness of a home-based exercise program using the Wii Fit system in patients with SLE. Fifteen sedentary African American women with SLE experiencing moderate to severe fatigue participated in a home exercise program using the Wii Fit 3 days a week for 30 minutes each for 10 weeks. A one-group pretest-post test design was used to evaluate the effectiveness of this program. Primary outcome measure was severity of fatigue. Secondary outcome measures were body weight, waist circumference, fatigue-related symptoms of distress, activity level, and physical fitness. At the completion of the 10-week Wii Fit exercise program, participants perceived fatigue severity as measured by the Fatigue Severity Scale to be significantly decreased (p = 0.002), and body weight and waist circumference were significantly reduced (p = 0.01). In addition, anxiety level, as measured by Hospital Anxiety and Depression Scale, and overall intensity of total pain experience, as measured by Short-form of the McGill Pain Questionnaire, were also significantly reduced (p < 0.05). Findings provide preliminary evidence that the Wii Fit motivates this population to exercise, which leads to alleviation of fatigue and reduced body weight, waist circumference, anxiety level, and overall intensity of total pain experience.