Pressure ulcer is one of the major challenges in hospitals; which endanger patient safety, prolonging hospital stay and contributed to disability and death. Data regarding to pressure ulcer prevention practice are very important to take action. However in Ethiopia, there are limited researches that have been conducted and there is clearly paucity of information on this regard. Hence, this study aimed to assess pressure ulcer prevention practice and associated factors among nurses in public hospitals of Eastern Ethiopia. A cross-sectional study was conducted among randomly selected 422 nurses who were working in the public hospitals of Eastern Ethiopia. Data were collected from the 1st February to the 1st March 2018 using pretested structured self-administered questionnaire and observational checklist. The collected data were entered into EpiData version 3.1 and exported to SPSS version 22.0 for analysis. Bivariable and multivariable logistic regression with crude and adjusted odds ratios along with the 95% confidence interval was computed and interpreted accordingly. Pressure ulcer prevention was determined based on mean calculation; a result above the mean value was categorized as good pressure ulcer prevention practice, and a P-value of <0.05 was considered to declare a result as statistically significant. In this study 51.9% (95% CI: 47.1%, 56.4%) of nurses were reported that they have good pressure ulcer prevention practice. On observation 45.2% of nurses were practicing proper pressure ulcer prevention activities. Pressure ulcer prevention practice were statistically associated with nurses with bachelor degree and above qualification level (AOR = 1.7, 95% CI: 1.02, 2.83), availability of pressure-relieving devices (AOR = 2.2, 95% CI: 1.34, 3.63), being satisfied with their job (AOR = 1.65, 95% CI: 1.09, 2.52) and good knowledge (AOR = 2.3, 95% CI: 1.48, 3.55). In this study the self-reported practice and results from observation was substantially low. Continuing education and training should be considered for nurses to enhance their practice regarding pressure ulcer prevention practice.