Irrigated durum wheat is a staple food crop that occupies important areas in Tunisia. However, its performance remains weak, with an average national yield of no more than 7 tons ha−1 and low profitability. Overall, on-farm wheat production will need to increase considerably to meet future demand and ensure minimum profitability for farmers. To this end, this study aims to identify the main levers for improving durum wheat crop performance. For this purpose, we have developed a regional bio-economic model by linking a biophysical model (CROPSYST) with an economic optimization model (MORBIT). CROPSYST was used to establish a database with a view to determining the relationships between farming practices, durum wheat yields, and water productivity within a context of high climate variability. The database was then integrated into a MORBIT model that analyzed the effects of farming practices on durum wheat performance and regional profits. Three scenarios related to irrigation control and the increase in durum wheat prices were developed. The results showed that reconciling irrigation practices with economic policies is the best alternative to improve durum wheat performance and increase profits at a regional level.