Background: Colchicine has been proposed as a cytokine storm-blocking agent for COVID-19 due to its efficacy as an anti-inflammatory drug. The findings of the studies were contentious on the role of colchicine in preventing deterioration in COVID-19 patients. We aimed to evaluate the efficacy of colchicine in COVID-19-hospitalized patients. Design: A retrospective observational cohort study was carried out at three major isolation hospitals in Alexandria (Egypt), covering multiple centers. In addition, a systematic review was conducted by searching six different databases for published studies on the utilization of colchicine in patients with COVID-19 until March 2023. The primary outcome measure was to determine whether colchicine could decrease the number of days that the patient needed supplemental oxygen. The secondary outcomes were to evaluate whether colchicine could reduce the number of hospitalization days and mortality rate in these patients. Results: Out of 515 hospitalized COVID-19 patients, 411 were included in the survival analysis. After adjusting for the patients’ characteristics, patients not receiving colchicine had a shorter length of stay (median: 7.0 vs. 6.0 days) and fewer days of supplemental oxygen treatment (median: 6.0 vs. 5.0 days), p < 0.05, but there was no significant difference in mortality rate. In a subgroup analysis based on oxygen equipment at admission, patients admitted on nasal cannula/face masks who did not receive colchicine had a shorter duration on oxygen supply than those who did [Hazard Ratio (HR) = 0.76 (CI 0.59–0.97)]. Using cox-regression analysis, clarithromycin compared to azithromycin in colchicine-treated patients was associated with a higher risk of longer duration on oxygen supply [HR = 1.77 (CI 1.04–2.99)]. Furthermore, we summarized 36 published colchicine studies, including 114,878 COVID-19 patients. Conclusions: COVID-19-hospitalized patients who were given colchicine had poorer outcomes in terms of the duration of supplemental oxygen use and the length of their hospital stay. Therefore, based on these findings, the use of colchicine is not recommended for COVID-19-hospitalized adults.