Wound infection plays an important role in the development of chronicity by delaying wound healing, prolonging hospital stay, increasing treatment cost and is responsible for significant morbidity. The aim of this study was to investigate the bacterial epidemiology, multi-drug resistance, and associated risk factors for wound infection at health institutions in Northeast Ethiopia. A facility-based cross-sectional study was conducted from February to April 2021. Demographic, clinical, and risk factor variables were collected using a structured questionnaire. Swabs/pus from wound were collected using sterile applicator swab. Specimens were inoculated on culture media and bacterial isolates were identified using microbiological techniques. Antimicrobial susceptibility test was performed using Kirby–Bauer disc diffusion method. Statistical analysis was done using SPSS software. A total of 229 participants were included in this study. A total of 170 bacterial isolates (74.2%) were isolated. The predominant isolates were S. aureus 80 (47.05%), followed by P. aeruginosa 29 (17.05%), E. coli 22 (12.94%), and Klebsiella spp. 16 (9.41%). Tetracycline (71.7%), clindamycin (15.2%), erythromycin (30.4%), penicillin (80.4%), and co-trimoxazole (80.4%) resistance rates were observed among Gram positive bacterial isolates. The overall prevalence of multi-drug resistance was 71%. Hence, improving the laboratory setup for culture and drug susceptibility testing is recommended for effective treatment of wound infection and to improve infection prevention and control practices in healthcare settings.