Interest in desalination to provide irrigation water is on the rise, but there are few tools enabling consideration of feasibility based on both crop responses and economic parameters. We present a biological-physical model for crop response to salinity coupled with economic calculations of farm based costs and benefits to determine profitability of irrigation of various crops in Israel as a function of water salinity. We then evaluate the economic feasibility of investment in farm- or community-scale desalination plants to supply high quality water as an alternative to irrigation with brackish water. The predicted profit from production of high-value, salinity-sensitive crops irrigated with either pure desalinated or desalinated blended with locally available brackish water was high enough to justify desalination for agriculture at prices expected in the market today, at least for mid- to large-capacity scale plants ( > 1 MCM/yr). The coupled model, accessible as an online application (http://app.agri.gov.il/AnswerApp/) was demonstrated as an effective tool to evaluate the sensitivity of any or all variables affecting crop profitability, combining both sound agronomic, biological and physical understanding of crop growth and response processes with sound economic data and considerations.