Background: Surgical Site Infections (SSIs) are among the frequently reported healthcare-acquired infections worldwide. Successful treatment of SSIs is affected by the continuous evolvement of drug-resistant microbes. This study investigated the incidence of SSIs, identifying the major etiologic agents and their drug resistance patterns in Yekatit 12 Hospital, Ethiopia. Methods: A cross-sectional study was conducted on 649 patients who underwent surgery at Yekatit 12 hospital from April 2016 to April 2017. Socio-demographic and clinical data were collected from each patient on admission. After surgery, they were followed for SSI occurrence. SSI was initially diagnosed by a senior surgeon based on standard clinical criteria and then confirmed by culture. Isolates were tested for drug resistance according to the clinical and laboratory standards institute guideline. Results: Of the 649 study participants, 56% were females. Their age ranged from 9 months to 88 years with a median age of 37 years. The incidence of culture-confirmed SSI was 10.2% (66/649) where 73 isolates were recovered. About two-third of the isolates were Gram-positive bacteria. Staphylococcus aureus was the most frequently isolated (27/73, 37%) followed by Coagulase-negative staphylococci (18/73, 24.7%), Escherichia coli (11/73, 15.1%) and Klebsiella species (10/73, 13.7%). About 89% and 44% of S. aureus isolates were resistant to penicillin and trimethoprim-sulfamethoxazole, respectively. MRSA constituted 11% of the S. aureus isolates. All the Gram-negative isolates were resistant to ampicillin and trimethoprim-sulfamethoxazole but susceptible to amikacin and meropenem. Klebsiella species showed 70-100% resistance to ceftazidime, cefuroxime, augmentin, chloramphenicol, ciprofloxacin, cefepime and gentamicin. About 82% of E. coli isolates were resistant for chloramphenicol, cefepime, ceftazidime, augmentin, cefuroxime and 64% for gentamicin and ciprofloxacin. Conclusion: The incidence of surgical site infection in Yekatit 12 hospital is 10.2%. Most of the SSIs were due to Gram-positive bacteria. Gram-negative isolates showed high resistance to the most commonly prescribed drugs. No resistance was found for meropenem indicating the absence of carbapenem-resistant bacteria. SSI treatments should be guided by culture and drug resistance test. Better infection prevention practices and continuous surveillance of antimicrobial resistance in the hospital are recommended for better patient care.