Low soil moisture content and soil fertility are the major problems constraining productivity of potato (Solanum tuberosum L.) in the eastern highlands of Ethiopia. Therefore, a field experiment was conducted to investigate the effect of drip irrigation regimes and fertilizer rates on tuber yield, as well as nitrogen, phosphorus, and water use efficiencies of potato during the off-season of 2019/2020. The experiment was laid out as a split-plot design with three replications. Three levels of irrigation regimes, viz. 50%, 75% and 100% (full) of ETc were assigned to the main plots. Seven rates of fertilizer [control; 65 kg N + 242 kg NPS ha−1(recommended rate); 50% of the recommended N + 75% of the recommended NPS along with 10 ton FYM ha−1; 75% of the recommended N + 50% of the recommended NPS along with 10 ton FYM ha−1; 75% of the recommended rate of N and NPS along with 5 ton FYM ha−1; 75% of the recommended rate of N and NPS along with 10 ton FYM ha−1 and 111 kg N + 92 kg P2O5 ha−1] were assigned to the sub-plots. The results indicated that the optimum total tuber yield (48.38-ton ha−1) and marketable tuber yield (47.80 ton ha−1) were obtained in response to the application of 75% of the recommended rate of N and NPS along with 5 ton FYM ha−1 together with 75% ETc. These total and marketable tuber yields exceeded the total and marketable tuber yield obtained in response to 50% ETc together with no fertilizer application by about four-fold. The above-mentioned treatment combination also resulted in the optimum agronomic nitrogen and phosphorus use efficiencies. Water use efficiency was improved by 3 kg m−3 in response to the application of 75% of the recommended rates of N and NPS along with 5-ton FYM ha−1 together with 50% ETc compared to the same rate of the fertilizer treatment combined with 100% ETc. It is concluded that application of 75% ETc combined with 75% of the recommended rate of N and NPS along with 10 ton FYM ha−1 increased potato yield, water productivity and N and P use efficiencies in Haramaya district.