There is a growing literature on the effects of cancer caregiving on the well‐being of informal family caregivers. However, there has been little longitudinal research on caregivers of patients with the complex, rapidly‐changing disease of primary malignant brain tumor. Objective Our objective was to model longitudinal relationships between caregiver burden, social support, and distress within caregivers of patients with primary brain tumor. Methods Caregiver participants were recruited from a neuro‐oncology clinic. Caregiver questionnaire data, including sociodemographics, social support, depression, anxiety, and caregiving burden, were collected at 4 time points (diagnosis, +4, +8, and +12 mo). Using the stress process model as a guide, we hypothesized that early burden would predict later depression and anxiety, and this would be mediated by social support. Results Using data from 147 participants, we found support for the stress process model in caregivers of patients with primary brain tumor. Greater burden at diagnosis was associated with lower social support at 4 months, and lower social support was related to higher depression and anxiety at 8 months, as well as to changes in anxiety between 8 and 12 months. Conclusion We found evidence of the stress process model in caregivers of primary brain tumor patients unfolding over the course of a year after diagnosis. Our findings emphasize the potential importance of early programs for caregivers to ensure low initial levels of burden, which may have a positive effect on social support, depression, and anxiety.