Potato is a staple food crop and the most important agricultural commodity, which critically affects food security and economic stability in Hamadan Province, Iran. Ex-ante sustainability appraisal of new cropping systems and their comparisons with conventional systems can increase the efficiencies of innovations and changes within the production process. This study aimed to explore the sustainability levels of potato cropping systems in Hamadan Province, Iran. To this end, DEXi methodology was developed for the sustainability assessment of the cropping systems. For assessing the three dimensions of environmental, economic, and social sustainability in the four systems of traditional potato system (TPS), Quasi-industrial potato system (QIPS), industrial potato system (IPS), and government-promoted potato system (GPPS), five groups of features were utilized: (1) irrigation method; (2) seed placement; (3) farm machinery use; (4) agrochemical use; and (5) rotation. The impact assessments of the cropping systems were based on two, three, and two groups of ecological, social, and economic indicators, respectively. Employment, supply chain, protection, operational difficulty, productivity, profitability, input use, and biodiversity resulted in 21 basic indicators and 13 aggregated indicators, by which the cropping systems were described. The results revealed that GPPS with distinctive economic and social profiles could have a better overall sustainability despite the fact that some indicators like biodiversity could be negatively affected. Finally, three strategies were recommended for the sustainability of GPPS as follows: biodiversity enhancement, input substitution, and integrated water management.