Background and Objective: Low productivity of sweet potato in Ethiopia was associated with different factors among which inappropriate vine cuttings and area-specific fertilizer recommendations are the most important ones in the area. Thus, a field experiment was conducted during the 2020/21 cropping season at Boloso Sore, Wolaita, Southern Ethiopia to determine the optimum vine length and NPS fertilizer rate that gives the highest root yield in sweet potato. Materials and Methods: Treatments consisted of four vine cutting lengths (10, 20, 30 and 40 cm) and four NPS rates (0, 75, 150 and 225 kg haG 1 ) in factorial arrangement and laid out in Randomized Complete Block Design (RCBD) with three replications. Results: The ANOVA showed that the interaction effect of vine cutting lengths and NPS rates significantly (p<0.05) affected biomass yield, marketable, unmarketable and total root number per plant, marketable and total root yield. The main effect of vine cutting lengths and NPS rates affected days to 90% maturity, vine number, root length and diameter and root dry matter. The highest total root yield (56.73 t haG 1 ) and marketable yield (54.89 t haG 1 ) were achieved by vine length of 30 cm and 225 kg NPS haG 1 . The highest gross net benefit of 438,267.10 Birr with the highest marginal rate of return (99.40%) was recorded by 30 cm and 225 kg NPS haG 1 . Conclusion: Hence, based on the current investigation, it can be concluded that vine cutting length of 30 cm with an NPS fertilizer rate of 225 kg haG 1 showed superior performance in the Wolaita area.