There is limited understanding about variables associated with fatigue in late and very late life. The purpose of this study was to explore the longitudinal influences of personality and health behaviors on changes in fatigue. One hundred and seventy-eight participants of the Georgia Centenarian Study were part of this study. Multiple regression analyses were computed to assess the influence of personality, physical activity, stress management, and nutritional risk on fatigue after initial fatigue, self-reported health, and psychosocial variables were controlled for. Anxiety, physical activity, and nutritional risk had significant longitudinal effects on fatigue. Older adults who were anxious, less engaged in physical activity, and who had higher levels of nutritional risk were more likely to show increased fatigue levels. The results suggest that more clinical and research attention should be paid to changes of fatigue in older populations.