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Moringa oleifera (M. oleifera) is a fast-growing, drought tolerant tree which has recently been identified as one of the prospective sources of biodiesel and one of the plants which can play a prominent role in the fight against desertification. In order to accelerate the commercialization of M. oleifera-based biodiesel, this paper develops a two-stage optimization model for the design of an efficient M. oleifera biomass to biodiesel supply chain. In the first stage, a common weight data envelopment analysis (CWDEA) model is utilized to rank locations threatened by desertification and land degradation. The locations with high vulnerability are introduced as candidate locations into the second stage in which a mixed-integer linear programming model is proposed to systematically design and optimize the entire supply chain and determine the optimal strategic and tactical supply chain decisions. To illustrate the application of the developed model, a case study in semi-arid lands of Iran is conducted. The results indicate that M. oleifera biodiesel production is not competitive with petroleum-based fuels but there is considerable room for cost reduction through improvement in M. oleifera productivity and oil conversion rate. Moreover, the areas at risk of desertification can be reclaimed by an increase of only 5% in the total supply chain cost. (C) 2018 Elsevier Ltd. All rights reserved.