Background: Percutaneous exposure to blood and body fluids through contaminated needle sticks and sharps are serious occupational hazards for morbidity and mortality from infections from blood-borne pathogens among healthcare workers. However, limited studies have been conducted to identify factors associated with needle stick and sharp injuries among healthcare workers in the study area. Therefore, this study aimed at identifying factors associated with needle stick and sharp injuries among healthcare workers. Methods: Institution-based cross-sectional study was conducted among healthcare workers at health facilities in Dessie from January to March 2018. A simple random sampling technique was used to recruit 362 healthcare workers. Data were collected using a structured self-administered questionnaire. The association between dependent and independent variables was checked using binary logistic regression and p-value ≤0.05 was used as a cutoff point for significance. Results: The entire work time and one-year prevalence of needle stick and sharp injury among healthcare workers were 60.2% and 40.1%, respectively. Working in private hospital (AOR = 9.619, 95% CI: 2.476, 27.373), working in private clinic (AOR = 3.308, 95% CI: 1.038, 8.506), less work experience (AOR = 2.762, 95% CI: 1.381, 4.521), higher workload (AOR = 3.794, 95% CI: 2.268, 6.346) and all-time availability of sharp storage and disposal containers (AOR = 0.435, 95% CI: 0.215, 0.879) were significant predictors of needle stick and sharp injuries. Conclusion: Prevalence of needle stick and sharp injury was high. Working in private health institutions, less work experience, higher workload and all-time availability of sharp storage and disposal containers were significant predictors of needle stick and sharp injuries. Therefore, efforts have to be made to reduce the workload of healthcare workers and to available sharp storage and disposal containers all the time in the workplaces.