Introduction: COVID-19 related mortality is about 2%, and it increases with comorbidities, like hypertension. Regarding management, there is debatable evidence about the benefits of continuation vs. discontinuation of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEI/ARB). Aim: We performed a systematic review to assess the effects and safety of in-hospital discontinuation compared to continuation of ACEI/ARB in COVID-19 patients. Methods: We systematically searched on PubMed, Scopus, and EMBASE from inception to June 19, 2021. We included observational studies and trials that compared the effects and safety of continuing ACEI/ARB compared to discontinuing it in COVID-19 patients. Effects sizes for dichotomous variables were expressed as risk ratios (RR) and 95% confidence intervals. For continuous variables, effects were expressed as mean difference (MD). We used random effect models with the inverse variance method. We assessed certainty of evidence using the GRADE approach. Results: We included three open-label randomized controlled trials and five cohort studies. We found that the continuation group had lower risk of death compared with the discontinuation group only in the cohort group (RR: 0.46, 95% CI: 0.24–0.90), but not in the RCT group (RR: 1.22, 95% CI: 0.75–2.00). The ICU admission rate was significantly lower in the continuation group (RR: 0.46, 95% CI: 0.31–0.68) in the cohort group, but not in RCT group (RR: 1.03, 95% CI: 0.67–1.59). We did not find significant differences between groups regarding hospitalization length, hypotension, AKI needing renal replacement therapy, mechanical ventilation, new or worsening heart failure, myocarditis, renal replacement therapy, arrhythmias, thromboembolic events and SOFA AUC. The GRADE approach revealed that the certainty ranged from moderate to high level. Conclusions: There is no significant difference in mortality and other outcomes between continuation and discontinuation groups.