Cassava (Manihot esculenta Crentz), is a major staple food crop of the people in most parts of Africa, and plays an important role in terms of food security, employment and income generation for farm families. It is one of important root crops in Ethiopian diet; however there is no research work has been done on rate of nitrogen and potassium fertilizer. Rate of N and K fertilizer are the major factor in determining the quality and quantities of cassava. Thus, this experiment was carried on the influence of nitrogen and potassium fertilizer rate on yield and qualities of cassava at Arba Minch. Four levels of N (0, 46, 92 and 138 kg N ha−1) and three levels of K (0, 60, and 120 kg K ha−1) were arranged in factorial combination in a randomized complete block design (RCBD) with three replications. The results revealed that the main effects of nitrogen fertilizer rates influences all the studied parameters, while the main effect of potassium affects number of tubers per plant and tuber diameter. Interaction effect of N and K influences fresh tuber yield of cassava. The highest fresh tuber yield of cassava was achieved from the combination of 92 kg Nha-1 with application of 0 kg K ha−1, whereas the lowest fresh tuber yield of cassava was obtained from the combination of 0 kg N ha−1 with 0 kg K ha−1. The economic analysis showed that higher net benefit and marginal rate of return were obtained from the application of 92 kg N ha−1 with 0 kg K ha−1. In order to prevent excessive production costs, the use of 92 kg Nha-1 combined with the application of 0 kg K ha−1 is recommended.