Blood flow restriction exercise (BFRE), which partially restricts arterial inflow and occludes venous outflow to the limbs, has gained attention for its potential to elevate serum brain-derived neurotrophic factor (BDNF), a key mediator in the muscle-brain crosstalk leading to improvement of neuroplasticity, neurogenesis, and cognitive health. In this systematic review of five studies, participants included healthy young adults, older adults, and individuals with clinical conditions. Most investigations found that BFRE increased serum BDNF, with responses comparable to those elicited by high-intensity exercise. Proposed mechanisms center on the metabolic demands of BFRE, which may increase lactate and thereby trigger BDNF release. However, two studies showed no significant changes, possibly due to short exercise duration, insufficient training intensity, or age-related reductions in BDNF responsiveness. The small sample sizes and varied protocols across studies limit definitive conclusions. Nonetheless, BFRE may provide a valuable alternative for populations who cannot tolerate high mechanical loads, and it shows promise for enhancing neurotrophic support and potentially improving brain health. Larger, well-controlled trials are warranted to refine BFRE protocols and better understand optimal strategies for increasing BDNF and supporting neuroplasticity.