The main challenges of Tunisian arid areas is better understand desertification and better adapt decisions to uncertainties that arise in complex interactions between the socioeconomic and biophysical dynamics at different spatial and temporal scales. This understanding is increasingly necessary to better target actions and improve coping strategies. The objective of this work is to assess the vulnerability of natural resources and the risk of desertification at the local scale, in a case study (Oum Zessar watershed) located in the southeast of Tunisia. The assessment is carried out through an analysis of different human and biophysical causes and driving forces, such as natural resources uses and climate change. It is based on geographical (landscape), integrated (socio-economy, biophysics) and multi-actors (research-decision) approaches, associated with reproducible methods and models to assess the risk of desertification, and to better target future combating actions. The work led to the development of desertification risk indexes (based on spatial integration of biophysical and socioeconomic functioning through modeling), facing several scenarios of climate change and human pressure. It shows that the same level of risk in one place or another may have differentiated causes, which could help public policy in their fighting against desertification.