Metal-organic frameworks (MOFs) exhibit broad potential applications in the environmental, biomedical, catalyst, and energy fields. However, the currently existing data hardly shed light on their health risks before the MOFs' large-scale usage. In this context, we exploratively investigated the in vivo fate and effect of one representative cobalt-based zeolitic imidazolate framework (ZIF-67) at the nano- (60 nm) and submicron- (890 nm) scales. Different from submicron-scale ZIF-67 showing better biosafety, nanoscale particles manifested a neurodegenerative risk at the dose of no general toxicity, evidenced by the impairment of learning and memory ability and disordered function of the neuropeptide signaling pathway in a rat model. The involvement of oxidative damage and inflammatory processes in the neurotoxicity induced by ZIF-67 was discussed as well. These findings not only provide a wake-up call for the prudent applications of MOFs but also provide insight into the better design and safer use of MOFs for broader applications.