Case reports suggest an association between second-generation antipsychotics (SGAs) and serotonin syndrome (SS). The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) was analyzed to generate hypotheses about how SGAs may interact with pharmacological targets associated with SS. FAERS was integrated with additional sources to link information about adverse events with drugs and targets. Using Proportional Reporting Ratios, we identified signals that were further investigated with the literature to evaluate mechanistic hypotheses formed from the integrated FAERS data. Analysis revealed common pharmacological targets perturbed in both SGA and SS cases, indicating that SGAs may induce SS. The literature also supported 5-HT2A antagonism and 5-HT1A agonism as common mechanisms that may explain the SGA-SS association. Additionally, integrated FAERS data mining and case studies suggest that interactions between SGAs and other serotonergic agents may increase the risk for SS. Computational analysis can provide additional insights into the mechanisms underlying the relationship between SGAs and SS.