The SARS-CoV-2 virus gains entry into human cells by exploiting the angiotensin-converting enzyme 2 (ACE2), a key component known as the spike protein (S), as a point of entry. Initially, SARS-CoV-2 suppresses the natural function of ACE2, leading to a gradual decline in cell health. Additionally, individuals with cancer are considered more susceptible to COVID-19. This study investigates the expression patterns of ACE2 in colorectal cancer (CRC) patients with and without a history of COVID-19 infection. RT-PCR was used to analyze samples from both cancerous and adjacent non-affected colorectal tissues of 47 CRC patients, comprising two groups: 24 CRC patients with no history of COVID-19 and 23 CRC patients with a recent history of COVID-19 infection. Epithelial CR cells were isolated from both types of tissues and cultured to evaluate cell adhesion. Immunohistochemistry analyses were conducted to examine ACE2 protein expression using various ACE2 antibodies for both cell types. The study revealed ACE2 mRNA expression in all CRC tissues of patients with and without a history of COVID-19. ACE2 expression was significantly higher in CRC patients without a history of COVID-19. Notably, the non-affected colorectal cancer (NACRC) tissues of patients without a history of COVID-19 also showed ACE2 expression, whereas no ACE2 expression was detected in the biopsies of CRC patients with a positive COVID-19 history. ACE2 antibodies were employed to validate ACE2 protein expression at the mRNA level. COVID-19 appears to downregulate ACE2 expression in both CRC and NACRC tissues of CRC patients with a positive history of COVID-19 infection.