Introduction Mechanisms underlying social determinants of stroke and dementia are unclear and brain-derived neurotrophic factor (BDNF) may contribute as a molecular link. Methods Using the Framingham Study, we examined social relationship measures as predictors of higher serum BDNF level and cumulative incidence of stroke and dementia. Results Among 3294 participants, controlling for age and sex, isolation trended with lower BDNF (odds ratio = 0.69 [0.47–1.00]). Participants with more companionship had reduced risk for stroke (hazard ratio [HR] = 0.59 [0.41–0.83]) and dementia (HR = 0.67 [0.49–0.92]). Greater emotional support was associated with higher BDNF (odds ratio = 1.27 [1.04–1.54]), reduced dementia risk (HR = 0.69 [0.51–0.94], and among smokers, reduced stroke risk (HR = 0.23 [0.10–0.57]). Associations persisted after additional adjustments. BDNF partly mediated the total effect between emotional support and dementia risk. Conclusions Availability of social support appears to be associated with increased BDNF levels and, in certain subsets, reduce risk of subsequent dementia and stroke, thus warranting study of these pathways to understand their role in neuroprotection.