It remains unknown whether statin therapy in combination with ezetimibe is a beneficial and equivalent alternative to statin monotherapy in reducing proinflammatory cytokines. In the present systematic review and meta-analysis, we aimed to assess the effect of combination therapy with statins and ezetimibe on some proinflammatory cytokines. Databases, including MEDLINE, SciVerse, Scopus, and Clarivate Analytics Web of Science databases, were searched up to February 2022, for terms related to combination therapy with statins and ezetimibe and proinflammatory cytokines. The quality of the included studies was evaluated with Cochrane risk of bias tool 1, and weighted mean difference [WMD] and SD of changes were used for meta-analysis. The results were expressed as differences in means and 95 % CIs with an inverse variance and a random-effects model. Finally, 12 studies [13 arms] were included in the qualitative and quantitative synthesis. The average patient's age ranged from 49.3 to 71 years, and the duration of intervention lasted seven days to 12 months. Overall, our result did not show any significant reduction in interleukin-1beta (IL-1β) (3 randomized controlled trial studies (RCTs), 292 participants, WMD: -0.4 pg/ml; 95 % CI: -1.3, 0.4, P = 0.3, I2 = 93.1 %, P < 0.001), tumor necrosis factor-alpha (TNF-α) (4 RCTs, 199 participants, WMD: -0.3 pg/ml; 95 % CI: -0.8, 0.1, P = 0.1, I2 = 13.8 %, P = 0.3) and monocyte chemoattractant protein-1 (MCP-1) (4 RCTs, 216 participants, WMD: -7.8 pg/ml; 95 % CI: -18.5, 2.8, P = 0.1, I2 = 30.8 %, P = 0.2). However, there was a significant reduction in interleukin-6 (IL-6) (9 RCTs, 514 participants, WMD: -1.4 pg/ml; 95 % CI: -2.4, -0.3, P < 0.007, I2 = 97.1 %, P < 0.001) and interferon-gamma (IFN-γ) (2 RCTs, 78 participants, WMD: -0.2 pg/ml; 95 % CI: -0.4, -0.1, P < 0.001, I2 = 0 %, P = 0.7). Following subgroup analysis, there was a significant reduction in IL-6 in the age group ≥ 60 years and the Asian population. Statin therapy in combination with ezetimibe causes a significant decrease in IL-6 and IFN-γ, and the reduction in IL-6 is significant in ≥ 60 years and the Asian population.