Ethiopia is intensifying efforts to boost wheat production with effective nitrogen (N) and phosphorus (P) management. However, low soil fertility and the lack of recommendations on optimal N and P application rates remain major constraints limiting wheat production. The effects of different N and P nutrient rates on the yield and nutrient uptake of bread wheat were evaluated on Vertisols of Moretina Jiru District, North Shewa Zone, Amhara Region, Ethiopia. The study was conducted using a factorial arrangement of treatments in Randomized Complete Block Design (RCBD) with three replications. The treatments were five N rates (69, 115, 161, 207, and 253 kg ha-1 ), three phosphorus rates in the form of P2O5 (46, 69, and 92 kg ha-1 ), and one control (0N- 0P2O5) treatment. Data were collected on growth, yield parameters, nutrient uptake of N and P, soil sampling and analysis, and analyzed using R statistical software version 4.3. The results showed that wheat grain yield was highly significantly affected by N rates (p<0.001) and significantly (p<0.05) by P rates, with the highest grain yield being five times greater than the control. Applying N or P alone significantly increased wheat grain yield, but their interaction did not affect the grain yield. The main effects of N and P, and their interaction, significantly influenced nutrient use efficiency. Both higher N rates and the combined application of N and P improved P use efficiency. Application of 253 kg N ha-1 resulted in the highest grain yield (4891 kg ha-1 ), straw yield (6690 kg ha-1 ), soil plant analysis development (SPAD) value (47.96), total N uptake (113.50kg ha-1 ), total P uptake (44.12 kg ha-1 ) and protein content (10.82%) of wheat compared to the application of other N rates. The optimum P2O5 rate was 69 kg P2O5 ha-1 which resulted in the highest grain (3869 kg ha-1 ) and straw yields (5210 kg ha-1 ). Moreover, the economic analysis showed that the combined application of 253 kg N with 69 kg P2O5 ha-1 was profitable having the highest Benefit:Cost ratio value of 3.60. Therefore, combined application of 253 kg N ha-1 and 69 kg P2O5 ha-1 was the optimum rate and recommended for wheat production on Vertisols of Moretina Jiru district and similar agroecologies and moisture domains until further N rate is determined based on multilocation studies.