OBJECTIVE Cannabis use has increased among older adults, yet the neurocognitive effects in this demographic remain unclear. Prior work has suggested cannabis may increase brain volume in areas rich in cannabinoid (CB1) receptors, though negative effects are often reported in adolescents. This study sought to clarify the relationship between cannabis use and brain health among middle-aged and older adults. METHODS Using data from the UK Biobank, which includes health information from over 500,000 adults, associations between cannabis use, regional brain volume, and cognition in participants aged 40-70 years (mean age = 54.5) were evaluated. RESULTS Lifetime cannabis use was positively associated with regional brain volume in CB1-rich regions, including the caudate, putamen, hippocampus, and amygdala. Greater lifetime use was also linked to better performance in learning, processing speed, and short-term memory. Individuals reporting use limited to adolescence also showed larger regional volumes and better cognitive performance than non-users. Sex differences in cannabis effects on brain volume and cognition were also observed. CONCLUSIONS Results highlight that cannabis may influence brain health differently across the lifespan, potentially offering protective effects in older age while posing risks earlier in development. Protective effects may result from endocannabinoid-mediated modulation of inflammation, immune function, and neurodegeneration. Observed sex differences likely reflect variation in the endocannabinoid system and underscore the importance of considering sex as a biological variable in studies of cannabis and brain health.