Potato has multiple benefits and thus can play a vital role in ensuring food security in Ethiopia. However, for diverse reasons, its productivity is low. The farming systems in Ethiopia in which potato is grown, are predominantly mixed farming systems. Most of the research in Ethiopia is focused on crop-specific constraints and thus there is limited research in which the interrelations between crop and livestock management practices are investigated. There is also not enough research focused on combined analysis of soil nutrient and animal feed balances and agronomic and socioeconomic efficiencies at farm level. This study assessed production constraints and agronomic and socioeconomic sustainability of the farming systems in South Ethiopia and explored the possible synergetic options to alleviate major constraints. More specifically, the study intended to quantify the variation in input and output among farms, to identify constraints hindering expansion of potato production, to evaluate the sustainability of the farming systems at farm level, to identify constraints of sustainable intensification, and to explore synergetic solutions for the major constraints. Different research approaches were used ranging from lab analysis, household surveys, group discussions, to farm surveys. Results showed that constraints related to input and product use in potato production vary across households indicating a need for a pluriform advisory model recognizing (and building upon alleviation of) the diversity of constraints identified in this analysis. The sustainability of the farming system is constrained by low agricultural productivity, low soil fertility, poor labour efficiency and limited economic return associated with improper crop rotation, inappropriate soil fertility management practices, shortage of animal feed, labour- and economically inefficient farm practices and labour shortage. However, there is ample scope to overcome the major constraints and simultaneously to optimize farm management. The core messages of the study can be summarized as follows: 1) the current potato production is characterized by low productivity and economic returns due to various socioeconomic, agronomic and biological factors; 2) the soil fertility is low and there is uneven distribution of nutrients over plots with relatively high fertility levels in the homestead areas; 3) the current labour shortage can be attributed to mainly inefficiency of agricultural management practices and labour migration to towns for economic reasons indicating that the farming system is not sustainable in terms of labour; 4) considering the direct return from animal production, most of the farms had very low gross margin with the current management system and this reduced the overall operating profit of farms. The low return from animal rearing was offset by the relatively high profit from crop production indicating the benefit of mixed farming system in sustaining agricultural production; and 5) each farm can have a wide range of optimized solutions mainly through introduction of improved technologies and subsequent redesigning of the farm managements. In general, the findings of the current study indicate that it is worthwhile to assess the sustainability of agricultural production in different farming systems and agro-ecologies of Ethiopia. In addition, the combined effect of introducing improved agricultural technologies and subsequent reconfiguring the farm management is very crucial to increase and sustain agricultural production.