Background: This study evaluated polyneuropathy as an immune-related adverse event following immune checkpoint inhibitor therapy and examined clinical factors associated with its development. Methods: We included patients who received immune checkpoint inhibitors in the All of Us Controlled Tier v8 dataset between December 2012 and September 2023. Variables included age, sex, race, alcohol use, smoking status, hypertension, diabetes mellitus, neuropathy-associated anticancer agents, and immune checkpoint inhibitor regimens. Associations were assessed using chi-square tests, and significant variables were entered into multivariable logistic regression models. Results: Among 998 treated patients, 202 developed polyneuropathy, yielding an incidence of 20.2%. In unadjusted analyses, polyneuropathy was associated with sex, hypertension, and platinum- and taxane-based chemotherapy. In multivariable analyses, female sex (adjusted OR 1.47, 95% CI 1.05–2.05), hypertension (adjusted OR 1.62, 95% CI 1.13–2.34), and taxane-based chemotherapy (adjusted OR 1.71, 95% CI 1.14–2.59) remained independently associated with increased risk. Conclusions: Female sex, hypertension, and taxane-based chemotherapy were independent risk factors for polyneuropathy in patients receiving immune checkpoint inhibitors, highlighting the need for risk stratification and careful monitoring.