Background Clinical anastomosis leakage leads to increased hospital costs, lengths of stay, readmissions, reoperations, and death. Therefore, this study aimed to assess clinical anastomotic leakage and associated factors among patients who had intestinal anastomosis in Northwest referral Hospitals, Ethiopia. Method A retrospective cross-sectional study design was conducted among 411 randomly selected patients. The patient’s medical records from February 2017 to February 2020 were used. The date range during which patients’ medical records were extracted was from March 1 to June 2020. Patient medical record charts and data extraction sheets were used to collect the data. Data was entered into EPI—DATA version 3.1 and exported into SPSS version 25 for analysis. Binary and multiple logistic regression analysis was used to assess the association between dependent and independent variables. P-value of less than 0.05 and odds ratio with 95% CI were used to declare the presence of association. Results The response rate of the study was 99.8%. Of 411 patients, 38 (9.2%) patients developed clinical anastomotic leakage. Age group 0–10 years (AOR = 6.85 95% CI: 1.742–26.97), emergency presentation (AOR = 3.196 95% CI: 1.132–9.025), and pre-operative comorbid disease (AOR = 7.62 95% CI: 2.804–20.68) were significantly associated with anastomotic leak. Conclusions Clinical anastomotic leakage is higher than the expected rate (4.9%-7.2%). Age, emergency presentation, and comorbidities were associated with clinical anastomotic leak. Hence, attention to early identification of risk factors and providing optimal pre-operative, operative, and post-operative care is necessary.