Introduction The often-cited mechanism linking brain-derived neurotrophic factor (BDNF) to cognitive health has received limited experimental study. There is evidence that cognitive training, physical exercise, and mindfulness meditation may improve cognition. Here, we investigated whether improvements in cognition after these three types of structured interventions are facilitated by increases in BDNF. Methods A total of 144 heathy older adults completed a 5-week intervention involving working memory/cognitive training, physical exercise, mindfulness meditation, or an active control condition. Serum BDNF levels and Digit Symbol Test (DST) performance were measured pre- and post-intervention. Results Linear mixed models suggested that only the cognitive training group demonstrated augmentation of BDNF and DST performance relative to the control condition. Path analysis revealed that changes in BDNF mediate intervention-related improvement in task performance. Regression analyses showed that, across all intervention conditions, increased BDNF levels were associated with increased DST scores. Discussion This study appears to be the first to suggest that BDNF helps mediate improvements in cognition after working memory training in healthy older adults. Highlights Older adults were randomized to physical activity, mindfulness, cognitive training (computerized cognitive training (CCT), or control. CCT, but no other condition, led to increased serum brain-derived neurotrophic factor (BDNF) levels. CCT led to improvement on the untrained Digit Symbol Test (DST) of speed/working memory. Path analysis: increases in BDNF mediate intervention-related improvement on DST. Increases in BDNF associated with improved DST across all experimental groups.