The impact of fertilizer of N and P on the yield of sesame in north-western Ethiopia was investigated. Field experiments were conducted in 2010 and 2011. Six levels of urea and six levels of di-ammonium phosphate were applied using a factorial completely randomized block design. Application of N and P increased the plant height, the number of capsules plant−1, and the yield ha−1. The number of days to flower decreased with increasing rates of nitrogen. The number of days to maturity was largest (91 days) at a rate of 23 kg N ha−1. Applying 92 kg N ha−1 resulted in a yield of 917.8 kg ha−1 and a plant height of 104 cm. An application of 92 kg P ha−1 with 36 Kg N ha−1 gave a yield of 908 kg ha−1 and a plant height of 103.4 cm. The interaction between N and P significantly affected the number of days to flower, plant height, the number of capsules plant−1, and yield ha−1. Applying 128 kg N ha−1 and 92 kg P ha−1 gave the biggest yield (1043 kg ha−1). However, application of 41 kg N ha−1 and 46 kg P ha−1 gave the largest marginal rate of return.