As one of the vital nutrient factors in central nervous system (CNS), brain-derived neurotrophic factor (BDNF) can significantly attenuate neuron damage and promote neurogenesis. Nevertheless, little research has been conducted on regulating the effect of BDNF on the inflammatory response after traumatic brain injury (TBI). In this study, we used BDNF fused with a collagen-binding domain (CBD-BDNF) to maintain a sufficient concentration of BDNF in the TBI hemisphere, and then, the regulatory effects of BDNF and CBD-BDNF on the inflammatory response of microglia were investigated both on a TBI mice model in vivo and LPS-stimulated microglia experiment in vitro. The results revealed that BDNF and CBD-BDNF had similar effects on attenuating the pro-inflammatory reactions but promoting anti-inflammatory responses of microglia induced by LPS in vitro. Furthermore, CBD-BDNF significantly improved the neurological behaviours of TBI mice and alleviated the inflammatory reaction after TBI, while BDNF had weaker effects compared with those of CBD-BDNF. Additionally, the TrkB inhibitor K252a significantly inhibited the above effects of CBD-BDNF. In conclusion, CBD-BDNF can promote the anti-inflammatory function of microglia and neurological recovery of TBI mice through TrkB signalling. © 2020 Royal Pharmaceutical Society.