Background Multi-drug resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa are major causes of nosocomial infections globally. They are the current World Health Organization critical priority pathogens for resistance, Antimicrobial resistance (AMR) surveillance and discovery of new antibiotics. However, there is paucity of data on nosocomial infections (NIs) caused by such superbugs in Ethiopia. Therefore, this study determined the magnitude and profile of nosocomial MDR A. baumannii and P. aeruginosa infections among patients hospitalized at Felegehiwot referral hospital, Northwest Ethiopia. Methods A cross-sectional study was conducted at Felegehiwot referral hospital from April 1 to July 31, 2018. A total of 238 patients with blood stream, urinary tract and surgical site NIs were enrolled conveniently. Either blood, urine and wound swab specimens were collected and processed using standard bacteriological procedures. A. baumannii and P. aeruginosa isolates were identified using standard bacteriological techniques and confirmed by automated Vitek2 Compact. Antimicrobial susceptibility testing on isolates was performed using the disk diffusion technique. The results were interpreted as per the standard zone sizes of Clinical and Laboratory Standards Institute.Chi-square test was done to determine associations among variables. P value < 0.05 was considered statistical significant. Results The median age of participants was 29 years. Overall,20(8.4%) of patients had nosocomial MDR A. baumannii and P. aeruginosa infections. The proportion of nosocomial MDR blood stream, urinary tract and surgical site infections were 13(8.9%), 5(8.3%) and 2 (6.3%), respectively. Patients with NI had lower mean age (24.9 years) (P = 0.035). All isolates of NIs were from patients with intravenous catheterization. The frequency of NI was 9(3.8%) for MDR A. baumannii and 11(4.6%) for MDR P.aeruginosa. A. baumannii and P. aeruginosa isolates were 100% MDR. All isolates of A. baumannii and P. aeruginosa were 100% resistant to ampicillin and piperacillin.A. baumannii isolates were 33.3 and 44.5% resistance against meropenem and ciprofloxacin, respectively while P.aeruginosa isolates revealed 36.4 and 45.5% resistance against ciprofloxacin and meropenem, respectively. Conclusions Health care associated infections of MDR A.baumannii and P. aeruginosa are critical problems in the study area. Therefore, urgent focused interventions required to contain the spreading of MDR NIs. Treatment of NIs for patients on health care should be guided by antimicrobial susceptibility testing.