Agriculture is one of the most vulnerable sectors to climate change. The current vulnerability assessments through traditional fragmented sectoral methods are insufficient to capture the effects on complex agricultural systems. Therefore, the traditional methods need to be replaced by integrated approaches. The objective of this study is to propose a holistic vulnerability assessment method for agricultural systems. By aggregating both agro-ecological and socio-economic information, we develop an agricultural systems vulnerability index (ASVI) which allows for: (i) a classification of geographical units according to their vulnerability level; (ii) an identification of key determinants of vulnerability for each unit; (iii) an assessment of adaptation policy scenarios considering their effects on the sustainability of the analysed systems. The proposed method is applied in the Khorezm region of Uzbekistan -a representative irrigated agricultural region in the Lower Amu Darya river basin. A decision support tool is used to facilitate multi-criteria decision analysis, including the computation of the index and performing sensitivity analysis of the results. The assessment for Khorezm reveals significant spatial differences of vulnerability levels due to a variation of contributing factors, e.g. natural resources, water productivity, rural-urban ratio. It reveals also that feasible land and water management policies could reduce the vulnerability in Khorezm, particularly in the districts with the poorest agro-ecological conditions. Overall, the proposed method could support national and local authorities in the identification of sustainable adaptation policies for the agriculture sector.