With immunotherapy historically focused on cutaneous melanoma, there has been a new wave of systemic medications available for treating non-melanoma skin cancers including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and Merkel cell carcinoma (MCC). The immune checkpoint inhibitors approved by the FDA target programmed cell death protein 1 (PD-1) and the Hedgehog (Hh) signaling pathway. These medications have expanded treatment options; however, side effects are an important consideration. We used the FDA Adverse Events Reporting System (FAERS) to characterize the most prevalent, real-world side effects experienced by patients on these agents. Muscle spasms (23.45%), alopecia (16.06%), ageusia (12.02%), taste disorder (11.91%), and fatigue (11.67%) were the five most common side effects reported with medications used for BCC treatment. Logistic regression analysis showed males on vismodegib for BCC having greater odds of experiencing muscle spasms (aOR 1.33, P<0.001) and ageusia (aOR 1.34, P<0.001) versus females, who were more likely to exhibit alopecia (aOR 1.82, P<0.001) and nausea (aOR 1.96, P<0.001). With SCC treatment, the 5 most reported adverse events were fatigue (5.58%), rash (3.59%), asthenia (3.59%), pruritus (3.19%), and pyrexia (2.79%). Patients taking cemiplimab-rwlc for BCC compared to SCC were more likely to experience disease progression (aOR 10.98, P=0.02). With medication labels providing an excessively daunting list of side effects, we characterize practical side effects seen in patients receiving systemic treatments for non-melanoma skin cancers. J Drugs Dermatol. 2024;23(5):301-305. doi:10.36849/JDD.7968.