This paper shows how system design determines sustainability outcomes of cassava bioethanol production in Colombia. The recovery of the energy contained in by-products is recommended as compared to single product production. In particular, this study assesses the energy, greenhouse gases, water, and land use performance of alternative cassava cascades working at different scales, highlighting the implications of including anaerobic digestion technology in the chain. The centralized systems showed a poorer energy and greenhouse gases performance as compared to decentralized ones in part due to the artificial drying of cassava chips in the centralized facility. Under solar drying of cassava chips, systems with anaerobic digestion produced three to five times more energy than demanded and produced greenhouse gas savings of 0.3 kgCO2eq L EtOH-1. The water balance output depends upon the water reuse within the ethanol industry, which demands 21-23 L EtOH-1. In the anaerobic digestion scenarios, assuming liquid flows are treated separately, complete water recovery is feasible. Land use for cassava cultivation was calculated to be 0.27-0.35 ha tEtOH-1. The energy and water content of the material to digest, the options for digestate reuse, and the recovery of the methane produced are major considerations substantially influencing the role of anaerobic digestion within cassava cascade configurations.