Background <p>Porcine epidemic diarrhea virus (PEDV) infection induces severe intestinal disease in neonatal piglets, resulting in substantial economic losses to the swine industry. Despite the availability of vaccines, their limited efficacy and the lack of effective antiviral treatments underscore the need for alternative therapeutic approaches. Several studies have reported the antiviral activity of various drugs and compounds against PEDV. To systematically compare the efficacy of these agents, we conducted a systematic review and meta-analysis to evaluate the inhibitory effects of various drugs or compounds on PEDV replication in vitro using cell based- models.</p> Methods <p>A comprehensive literature search was conducted in PubMed, Web of Science and ScienceDirect, encompassing publications from the inception of each database to May 30,2025. Eligible studies primarily focused on the effects of pharmacological and combination interventions on PEDV replication in vitro. Changes in the tissue culture infectious dose (TCID50) served as the primary outcome measure, with standardized mean difference (SMD) used to quantify effect sizes.</p> Results <p>Thirty-two eligible studies involving 41 distinct drugs and 63 effect sizes were analyzed. A random-effects model revealed an overall SMD of -12.30 (95% confidence interval: -13.64 to -10.95) for the antiviral efficacy of drugs at safe concentrations. Moderate heterogeneity was observed (I²=64.2%, <i>P</i> &lt; 0.001), with subgroup analyses identifying cell type, viral strain, genotype, drug concentration and intervention duration as significant influencing factors (<i>P</i> &lt; 0.05). Intrinsic antiviral activity emerged as the primary source of heterogeneity. Quality assessment using BRISQ guidelines rated 15 studies as high quality and 17 as medium quality, while modified ROBINS-I classified 26 studies as low risk of bias and 6 as moderate risk. Publication bias was suggested by funnel plots and egger’s test. However, sensitivity analyses confirmed the robustness of the results.</p> Conclusion <p>Forty-one of drugs and compounds demonstrate effective inhibition of PEDV replication in vitro, with antiviral efficacy influenced by experimental variables and predominantly determined by intrinsic antiviral activity. These findings offer valuable guidance for optimizing the design of PEDV antiviral studies and contribute insights for future in vivo efficacy and mechanistic research.</p> Systematic review registration <p>Open science framework (<a href="https://doi.org/10.17605/OSF.IO/V4C8Y">https://doi.org/10.17605/OSF.IO/V4C8Y</a>).</p>