Aims: In this study, we aimed to identify the relationship between nursing practice environments (NPEs) and safety perceptions with patient safety culture (PSC) during COVID-19. Design: We conducted a quantitative, non-experimental, correlational, and cross-sectional study. We interviewed 211 nurses from Peru using two scales: PES–NWI and HSOPSC. We used the Shapiro–Wilk test and Spearman’s coefficient and estimated two regression models. Results: NPE was reported as favorable by 45.5% of the participants, and PSC was reported as neutral by 61.1%. Safety perception, the workplace, and NPE predict PSC. All NPE factors were correlated with PSC. However, safety perception, support of nurses subscale, the nurse manager’s ability, and leadership were predictors of PSC. Conclusion: To promote a safe work culture, health institutions should foster leadership that prioritizes safety, strengthens managers’ abilities, encourages interprofessional collaboration, and considers nurses’ feedback for constant improvement.