Pathogens, damaged cells, and toxic compounds stimulate the immune system to produce inflammatory markers, creating acute or chronic inflammation at different organ sites [1]. Although this is a vital physiologic process, uncontrolled inflammation that becomes chronic can result in various chronic inflammatory diseases, including diabetes, various cancers, cardiovascular diseases, etc. [2], [3]. Interestingly, the pathological role of inflammation has been implicated in the recent coronavirus disease 2019 (COVID-19) pandemic [4]. The primary inflammatory stimuli including C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), mediate inflammation by activating their related receptors [5], [6]. Finally, the downstream signaling pathways, including the mitogen-activated protein kinase (MAPK), nuclear factor Kappa-B (NF-κB), and Janus kinase signal transducer and activator of transcription (STAT), are activated [7], [8], [9]. It has been widely investigated and accepted that oxidative stress plays an important role in the pro-inflammatory effects [10], [11], [12]. Indeed, oxidative stress can occur due to the imbalance between pro-oxidants and anti-oxidants that disrupts the redox signaling pathways [13]. Antioxidants are able to reduce inflammation and oxidative stress at gene expression levels [14], [15]. Selenium (Se) is an important micronutrient that plays a role in seleno-enzymes as an antioxidant and anti-inflammatory with immuno-regulatory properties due to its role in selenoproteins, including; glutathione peroxidases (GPX), and thioredoxin reductase’s structure. Also, seleno-compounds, especially sodium selenite, have a role as a pro-antioxidant and have potential bactericidal or virucidal roles, may be apoptosis-reducing, and/or possess genomic action in inflammatory conditions[16], [17], [18], [19]. Moreover, the plasma concentration of selenoproteins, such as selenoprotein P, plays a role in endothelium protection and is significantly decreased in septic shock. Abundant research, utilizing different doses, duration, and administration routes, regarding the effect of Se supplementation on inflammation, has been published [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]; however, equivocal results have been reported. Therefore, the present systematic review and meta-analysis of published RCTs sought to evaluate the effect of Se supplementation on serum pro-inflammatory markers including CRP, IL-6, and TNF-α.