Read-across (RA) and quantitative structure-activity relationship (QSAR) are two alternative methods commonly used to fill data gaps in chemical registrations. These approaches use physicochemical properties or molecular fingerprints of source substances to predict the properties of unknown substances that have similar chemical structures or physicochemical properties. Research on RA and QSAR is essential to minimize the time, money, and animal testing needed to determine biological properties that are not currently known. This study developed a stacked ensemble quantitative read-across structure-activity relationship algorithm (enQRASAR) for predicting skin irritation toxicity based on negative log cell viability inhibition concentration at 50% (pIC50) against skin keratinocytes as the end point. The goodness-of-fit and predictability of this algorithm were validated using leave-one-out cross-validation and external test data sets. The results obtained were statistically reliable in terms of goodness-of-fit, robustness, and predictability metrics. Additionally, the developed model demonstrated a low prediction error when predicting FDA-approved drugs. These results confirm that the enQRASAR algorithm can be used to predict skin cytotoxicity of chemicals. Therefore, this model was publicly available to further facilitate toxicity predictions of unknown compounds in chemical registrations.