Background This study utilized data from the FDA Adverse Event Reporting System (FAERS) to investigate adverse drug events (ADEs) associated with avelumab, spanning from the third quarter of 2015 to the first quarter of 2024. Methodology We collected and normalized avelumab ADE data from Q3 2015 to Q1 2024. To ensure robust signal detection and accurate measurement of association strength, we employed key techniques, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM). These methods allowed for the comparison of event proportions, consideration of uncertainties, and adjustment for reporting variability, ensuring reliable signal quantification and analysis. Results In our review of 3,978 ADE reports, we classified unique preferred terms (PTs) into 22 systematic organ classifications (SOCs) to detail the range of avelumab-associated adverse reactions. The most commonly reported SOC was "General disease and administration site conditions," with 868 cases reported (ROR = 1.22, PRR = 1.17, IC = 0.23, EBGM = 1.17). The second was nervous system disorders (294 cases) (ROR = 0.9, PRR = 0.91, IC = 0.14, EBGM = 0.91). The incidence of "Injury, poisoning and procedural complications" was 253 cases (ROR = 0.52, PRR = 0.55, IC = 0.86, EBGM = 0.55). This rank highlighted significant differences in the frequency and risk indicators of these diseases. It is worth noting that PTs with strong signals detected included thrombocytopenia (n = 35, ROR = 4.98, PRR = 4.95, IC = 2.31, EBGM = 4.95), hypothyroidism (n = 31, ROR = 15.49, PRR = 15.38, IC = 3.94, EBGM = 15.36), and renal impairment (n = 23, ROR = 3.93, PRR = 3.91, IC = 1.97, EBGM = 3.91). Conclusions While avelumab offers significant therapeutic benefits, its use carries potential adverse effects. Clinicians must remain vigilant in monitoring patients, particularly for severe symptoms, such as thrombocytopenia, hypothyroidism, and renal impairment, to ensure prompt intervention and minimize risks. Early detection of these and other potential events will help healthcare providers better manage and mitigate the risks associated with avelumab treatment.