To evaluate the association between nurse staffing coverage and patient outcomes in a context of structural understaffing. This is a population-based, cross-sectional, multicenter study, including patient and staffing data from eight public hospitals from Catalonia, Spain. A total of 183,085 adult in-patients admitted to hospital wards and step-down units during 2016 and 2017. In-hospital mortality, 30-day hospital readmission, and three cluster nurse-sensitive adverse events: healthcare-acquired infections, failure to maintain, and avoidable critical complications. The study factor is safe nursing staffing equivalent to nurse staffing coverage > 90%. Average patient acuity was equivalent to 4.5 required nursing hours per patient day. The mean available nursing hours per patient day was 2.6. The average nurse staffing coverage reached 65.5%. Overall, 1.9% of patients died during hospitalization, 5% were readmitted within 30 days, and 15.9% experienced one or more adverse events. Statistically significant differences were identified for all patient outcomes when comparing patients safely covered (nurse staffing coverage > 90%) and under-covered (nurse staffing coverage < 90%). Increasing nurse staffing coverage to a safe level (> 90%) is associated with a reduction of the risk of death (RR: 0.41, 95% CI: 0.37-0.45), a decrease in the risk of hospital readmission (RR: 0.93, 95% CI: 0.89-0.97), and a reduction of nurse-sensitive adverse events (RR: 0.67, 95% CI: 0.66-0.69). Safe nurse staffing coverage acts as a protective factor for detrimental patient outcomes, significantly reducing the risk of in-hospital mortality, 30-day hospital readmission, healthcare-associated infections, failure to maintain, and avoidable critical complications. Further policy efforts are needed to guarantee a safe registered nurse staffing coverage.