Introduction: Colorectal Cancer (CRC) is a leading cause of death worldwide, and its incidence has been rising. It is important to identify novel markers that could predict the prognosis of the disease. Aim: To identify the impact of Programmed cell death-ligand 1 (PD-L1), Beclin 1, and Fascin 1 immunohistochemical expression on CRC behaviour and disease prognosis. Also, to assess the different surgical options (laparoscopic versus open) in the management of these patients. Materials and Methods: This cohort study included 72 cases of CRC, conducted in the Pathology, General Surgery, Internal Medicine, Clinical Oncology, and Medical Oncology Departments of the Faculty of Medicine, Zagazig University Hospitals, Egypt between June 2018 and June 2022. PD-L1, Beclin 1, and Fascin 1 expression were assessed immunohistochemically, and their prognostic significance were evaluated. Data were analysed using IBM Statistical Package for the Social Sciences (SPSS) 23.0 for Windows (SPSS Inc., Chicago, IL, USA) and NCSS 11 for Windows (NCSS LCC., Kaysville, UT, USA) in the Community Medicine Department, Faculty of Medicine, Zagazig University, Egypt. Results: A significant association was found between PD-L1 expression and grading (p-value=0.02), lymphovascular invasion, distant metastasis (p-value=0.001), peritoneal spread (p-value=0.002), tumour budding (p-value=0.005), lymph node metastasis, and American Joint Committee on Cancer (AJCC) stage (p-value<0.001). A significant association was also found between Beclin 1 expression and distant metastasis (p-value=0.001), lymphovascular invasion (p-value=0.004), lymphocytic infiltration (p-value=0.006), perineural invasion (p-value=0.01), peritoneal spread (p-value=0.002), and AJCC stage (p-value=0.007). A highly significant association between Fascin 1 expression and grading, lymphovascular invasion, tumour budding, lymph node metastasis, lymphocytic infiltration, perineural invasion, metastasis, peritoneal spread, and AJCC stage (p-value<0.001) was detected. In patients with negative PD-L1 or high Fascin 1 expression, survival rates were lower. Beclin 1 expression was not associated with a favourable prognosis (p-value>0.05). Conclusion: PD-L1, Beclin 1, and Fascin 1 expression are significantly elevated in CRC tissues and closely associated with adverse prognostic factors. PD-L1 and Fascin 1 expression have important prognostic value and may be of great help in identifying high-risk patients who will benefit the most from treatment.