<p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which is pathologically characterized by impairing the motor neurons, leading to the disorders of motor function. Aspirin (ASP) has the ability to increase the survival time of SOD1^G93A mice via concurrently reducing the activation of glial cells and restoring the number of neurons. Meanwhile, ASP treatment inhibited the activities of NF-κB pathway, which resulted in regulating the expression of complement system (CS), including C3, C1qb, and C4b in vivo. To reveal the inherent mechanisms, the in vitro experiments were carried out in SOD1^G93A protein- and lipopolysaccharide (LPS)-treated BV2 cells. The results demonstrated that SOD1^G93A protein or LPS induces the activation of NF-κB in BV2 cells, whose conditional medium induces the apoptosis of NSC34 cells. By blocking the activities of NF-κB by ASP, Bay 11–7082 or si NF-κB, the synthesis of CS molecules was suppressed, which results in alleviating the apoptosis of NSC34 cells. More importantly, Terminal complement complex (TCC) was identified to be the critical component of CS for mediating the effects of SOD1^G93A protein or LPS on inducing the apoptosis of neurons, which was inhibited by the ASP or Bay 11–7082. On the basis of these observations, our findings novelly revealed that ASP delayed the progression of ALS via inhibiting the activities of microglia in a NF-κB-dependent CS-deactivating mechanisms.</p>