Background Moral distress is a common challenge among professional nurses when caring for their patients, especially when they need to make rapid decisions. Therefore, leaving moral distress unconsidered may jeopardize patient quality of care, safety, and satisfaction. Aim To estimate moral distress among nurses. Methods This systematic review and meta-analysis conducted systematic search in Scopus, PubMed, ProQuest, ISI Web of Knowledge, and PsycInfo up to end of February 2022. Methodological quality of included studies was assessed using the Newcastle Ottawa checklist. (...) Data from included studies were pooled by meta-analysis with random effect model in STATA software version 14. The selected key measure was mean score of moral distress total score with its’ 95% Confidence Interval was reported. Subgroup analyses and meta-regressions were conducted to identify possible sources of heterogeneity and potentially influencing variables on moral distress. Funnel plots and Begg’s Tests were used to assess publication bias. The Jackknife method was used for sensitivity analysis. Ethical consideration The protocol of this project was registered in the PROSPERO database under decree code of CRD42021267773. Results Eighty-six manuscripts with 19,537 participants from 21 countries were included. The pooled estimated mean score of moral distress was 2.55 on a 0–10 scale [95% Confidence Interval: 2.27–2.84, I2: 98.4%, Tau2:0.94]. Publication bias and small study effect was ruled out. Moral distress significantly decreased in the COVID-19 pandemic versus before. Nurses working in developing countries experienced higher level of moral distress compared to their counterparts in developed countries. Nurses' workplace (e.g., hospital ward) was not linked to severity of moral disturbance. Conclusion The results of the study showed a low level of pooled estimated score for moral distress. Although the score of moral distress was not high, nurses working in developing countries reported higher levels of moral distress than those working in developed countries. Therefore, it is necessary that future studies focus on creating a supportive environment in hospitals and medical centers for nurses to reduce moral distress and improve healthcare. (shrink)