Hyperchloremia has negative consequences, such as increased proinflammatory mediators, renal dysfunction, and mortality in patients with septic shock. However, data on the effects of hyperchloremia on COVID-19 infections are scarce. The study aimed to investigate the effects of hyperchloremia on inflammatory markers, serum creatinine, hemoglobin levels, and outcomes in critically ill COVID-19 patients. A retrospective review of all adult patients admitted to the ICU at King Fahd University Hospital with a moderate to severe COVID-19 infection from January 2020 to August 2021 was performed. Serum chloride levels, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), creatinine, and hemoglobin levels were collected on the first and third days of ICU admission. Demographic data, oxygen support modality, ICU length of stay (ICU LOS), renal replacement therapy (RRT), and deaths were collected. Of 420 patients, 255 were included; 97 (38%) had hyperchloremia, while 158 (62%) did not. Hyperchloremic patients had a higher percentage of increases in ferritin (54.6%), CRP (6.2%), and LDH (15.5%) between the first and third days of admission, compared to non-hyperchloremic patients (43.7%, 6.3%, and 5.7%, respectively). The decrease in hemoglobin levels was similar in both groups (p=0.103). There was a significant association between hyperchloremia and an increase in serum creatinine (p<0.0001). Sixty-six (68%) patients required endotracheal intubation in the hyperchloremic group (p=0.003). The mortality rate was significant in the hyperchloremic cohort (p=<0.0001). Hyperchloremia was significantly associated with increased risks of kidney injury, endotracheal intubation, and death. However, hyperchloremia was not associated with increased ferritin, CRP, or hemoglobin decreases in critically ill COVID-19 patients.