The COVID-19 pandemic introduced unique challenges to healthcare systems, particularly in relation to patient safety and adverse events during hospitalization. There is limited understanding of COVID-19's association with some patient safety indicators (PSIs). This study aimed to investigate the impact of COVID-19 infection on the rate of PSI-3 events and its implications on quality metrics. We compared PSI-3 event rates between COVID-19-infected and uninfected patients and examined the clinical characteristics of COVID-19 patients experiencing PSI-3 events. This is a retrospective study at Mayo Clinic hospitals between January 2020 and February 2022, analyzing patients meeting PSI-3 denominator eligibility criteria. PSI-3 events were identified using AHRQ WinQI software. Patients were categorized based on COVID-19 status. Patient demographics, characteristics, and PSI-3 rates were compared. A case series analysis described clinical details of COVID-19 patients with PSI-3 events. Of 126,781 encounters meeting PSI-3 criteria, 8674 (6.8%) had acute COVID-19 infection. COVID-19-infected patients were older, more likely to be male, non-white, and had private insurance. PSI-3 rates were significantly higher in COVID-19 patients (0.21% versus 0.06%, P < 0.0001), even after risk adjustment (adjusted risk ratio, 3.24, P < 0.0001). The case series of 17 COVID-19 patients with PSI-3 events showed distinctive clinical characteristics, including higher medical device-related pressure injuries, and greater predisposition for head, face, and neck region. Acute COVID-19 infection correlates with higher PSI-3 event rates. Current quality indicators may require adaptation to address the pandemic's complexities and impact on patient safety. Further research is needed to comprehensively understand the intricate relationship between COVID-19 and patient outcomes.