BACKGROUND AND OBJECTIVE: With limited evidence connecting paradoxical inflammatory bowel disease (paradoxical IBD) to the newest biologics and Janus kinase inhibitors, our study aims to investigate the occurrence of paradoxical IBD induced by these agents in treating other immune-mediated inflammatory diseases (IMIDs). We aim to identify associated risk signals, the primary affected population, and the risk profile changes over time. METHODS: We performed disproportionality analysis to evaluate paradoxical IBD risk signals using data from the FDA Adverse Event Reporting System. Stratification analyses according to IBD subtype, age, gender, and agents' indications were performed. Weibull shape parameter (WSP) test was conducted to assess paradoxical IBD risk changes over time. Linkage disequilibrium score regression and Mendelian Randomization were employed to evaluate genetic correlations and causality between these agents' indications (i.e., non-IBD IMIDs) and IBD. RESULTS: This study included 3296 patients reporting 3407 occurrences of paradoxical IBD following using these agents as primary suspects. Among TNF blockers, consistent positive signals for paradoxical IBD were noted: Adalimumab (n = 1983, ROR [95%CI] = 1.55 [1.47-1.63]), Infliximab (n = 545, ROR [95%CI] = 2.12 [1.95-2.32]), Certolizumab Pegol (n = 342, ROR [95%CI] = 1.9 [1.71-2.12]), and Golimumab (n = 154, ROR [95%CI] = 1.64 [1.4-1.93]). Ustekinumab, an IL-12 and IL-23 antagonist, also showed a strong positive signal (n = 155, ROR [95%CI] = 2.03 [1.73-2.39]). Conversely, Upadacitinib, Tofacitinib (Janus kinase inhibitors), and Risankizumab (IL-23 antagonist) exhibited insignificant associations with paradoxical IBD. Crohn's disease (CD) is the mainly developing form. WSP analysis identified two temporal patterns of paradoxical IBD: early failure and random failure types. Significant genetic correlations between three IMIDs and IBD were uncovered, with psoriasis specifically found to causally elevate CD risk. CONCLUSIONS: This study identifies paradoxical IBD as a consistent positive signal across multiple IMID agents, predominantly manifesting as CD, potentially aiding in timely detection and therapeutic decision-making.