Introduction <p>Brain tumor symptoms may affect the patients’ caregivers. This study aimed to explore the mediation roles of hope and social support in the relationship between fatigue and burden in brain tumor caregivers.</p> Methods <p>This is a cross-sectional study on 280 caregivers of brain tumor patients. Adult Hope Scale, Zarit Burden Interview, Personal Resources questionnaire 85, and Multidimensional Fatigue Inventory were used. The mediator model by the SPSS Macro PROCESS (Model 4, and 6) was used.</p> Results <p>Over half of caregivers reported moderate fatigue and social support, with half experiencing moderate to severe caregiving burden. Moreover, 60.4% were moderately to highly hopeful. Significant relationships were found between fatigue and hope (<i>r</i>=-0.57, <i>p</i> &lt; 0.001), social support (<i>r</i>=-0.65, <i>p</i> &lt; 0.001), and burden (<i>r</i> = 0.63, <i>p</i> &lt; 0.001), as well as between hope and social support (<i>r</i> = 0.57, <i>p</i> &lt; 0.001). Fatigue, social support, and hope predicted the caregivers’ burden. The indirect effect of fatigue on burden by hope was significant (Effect = 0.16, 95% CI 0.02 to 0.30). The indirect effect of fatigue on burden by social support was also significant (Effect = 0.38, 95% CI 0.21 to 0.57). The indirect effect of fatigue on burden by hope and social support was significant (Effect = 0.12, 95% CI 0.04 to 0.21).</p> Conclusion <p>The results of this study showed that hope and social support should be improved in the caregivers of brain tumor patients. By conducting interventions in this field, it is possible that the burden of caregivers is decreased in situations with high fatigue.</p>