Epidemiological research has shown that a variety of circulating bioactive factors are associated with epilepsy, including macrophage colony-stimulating factor, interleukin-1β, and tumor necrosis factor-α. To further investigate the associations between epilepsy and 41 inflammatory cytokines, this Mendelian randomization was performed. This study presents genome-wide association study summary data on 41 inflammatory cytokines and epilepsy. Epilepsy incorporates generalized and focal epilepsy. A two-sample Mendelian randomization method was used. In order to analyze causal relationships between exposures and outcomes, the inverse variance-weighted method was mainly used. The findings suggested that increased levels of interleukin-1 receptor antagonists and interleukin-5 may be significantly associated with increased risks of focal epilepsy (beta: 0.080, P = .043; beta: 0.083, P = .015). In addition, regulated upon activation normal T cell expressed and secreted factor and Macrophage colony-stimulating factor may be significantly associated with generalized epilepsy (beta: 0.110, P = .042; beta: -0.114, P = .024). Furthermore, inflammatory cytokines such as interleukin-10, interleukin-1β, interleukin-1Ra, interleukin-7, tumor necrosis factor-α, and interferon-γ may be identified as the result of focal epilepsy (beta: 0.152, P = .031; beta: 0.214, P = .037; beta: 0.214, P = .047; beta: 0.222, P = .031; beta: 0.224, P = .025; beta: 0.161, P = .018). This study suggests that interleukin-5 and interleukin-1 receptor antagonists are potentially correlated factors with focal epilepsy etiology, macrophage colony-stimulating factor and regulated upon activation normal T cell expressed and secreted factor are potentially correlated factors with generalized epilepsy etiology, while several inflammatory cytokines possibly contribute to focal epilepsy development downstream.