Introduction: This study was conducted to evaluate the effects of replacing soybean meal (SBM) with slow-release urea (SRU) on milk production, nutrient digestibility, and blood parameters of Holstein dairy cows. Materials & Methods: In this regard, sixteen Holstein dairy cows weighing between 550-680 kg, yielding ~ 30 kg milk/d were randomly assigned to 4 dietary treatments (4 replicates or cows) in a 12-week study. Treatments consisted of i) control diet which included SBM as a protein source; ii) control diet supplemented with 0.5%, 0.75% and 1% SRU. In this regard, sixteen Holstein dairy cows weighing between 550-680 kg, yielding ~ 30 kg milk/d were randomly assigned to 4 dietary treatments (4 replicates or cows) in a 12-week study. Treatments consisted of i) control diet which included SBM as a protein source; ii) control diet supplemented with 0.5%, 0.75% and 1% SRU. Result:Feeding SRU did not have any significant effect on milk production(P>0.5), but milk production was higher for the cows fed 0.5% SRU. Crude protein (CP) digestibility was significantly different between treatments(P<0.05). Feeding SRU did not have any significant effect on organic matter (OM), ether extract (EE), non-structural carbohydrates (NSC) and Acid detergent fiber (ADF) digestibility(P>0.05). Also, glucose and very-low-density lipoprotein (VLDL) concentrations were not significantly affected by feeding SRU(P>0.05). Plasma cholesterol and triglyceride concentrations, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and blood urea nitrogen (BUN) concentrations were significantly different between treatments(P<0.05). Conclusion:Based on the results of this study, replacing SBM with SRU improves fiber and protein digestibility, microbial protein production, productive performance and finally reduces the productions’ costs.