Sorghum (Sorghum bicolor (L.) Moench) is an important cereal crop and stable food for the semi-arid small scale farming communities in the third world. Even though, it is highly adapted to different agro-ecological conditions, its yield is constrained by different factors including declining soil fertility and improper utilization of fertilizer. Results of the research conducted in Shire-Mytsebri Agricultural Research Center at Sheraro sub-site during the main cropping season of 2016 are presented in the paper. The aim was to investigate the effect of NPK; and blended fertilizer on nitrogen, phosphorus, and potassium uptake; and nutrient use efficiency of selected sorghum varieties. The treatments are comprised of factorial combination of ten levels of fertilizers including the recently recommended [N, P, Blanket recommendation (NP), NPK, NPS, NPKS, NPKSZn, NPKSZnB, NPKSZnB (after Agricultural Transformation Agency, ATA) and Control (0)]. Two sorghum varieties (Melkam and Dekeba) were tested in a Factorial Randomized Complete Block Design with three replications. The data were computed using four agronomic indices, which are commonly used to describe nutrient (N, P and K) uptake and use efficiency. The results indicate that there is a significant interaction effect of fertilizer treatments and sorghum varieties on majority of the parameters studied. Application of NPKSZn blended fertilizer significantly enhanced nutrient uptake and use efficiency. The highest total N (78.70 kg ha-1), P (51.19 kgha-1) and K (74 kg ha-1) uptake and use efficiency in Melkam variety treated by fertilizer contained NPKSZn brought higher yield (5541 kg ha-1). Increasing uptake of the major nutrient elements ensured ample nutrient availability for normal growth and high yield of sorghum. Thus, application of macronutrients in combination with micronutrients increased sorghum yield and concomitantly improved N, P and K uptake, and nutrient use efficiency for the sorghum varieties used in the study. Therefore, it is recommended that in the study area and other similar areas blended fertilizer 41N-46P-13.7K-9.25S-1.72Zn kg ha-1 be used to achieve higher yields.