This study investigated the effects of two soil moisture levels (SM) (30% and 70% soil available water) and three harvests (90 days, 118 days, and 151 days after seeding) on sweet (S506) and fiber (B133) sorghum genotypes under rain-sheltered conditions. Juice and bagasse-derived ethanol and their sum (EtOHBJ, EtOHB, and EtOHJ+B, respectively) were assessed. Water use efficiency (WUE) was determined for sorghum dry weight (DW) and EtOHJ+B. S506 had similar DW, but higher sugar content than B133, resulting in higher EtOHJ (+32%) and EtOHJ+B (+9%). High SM-enhanced DW, juice and sugars content, determining a strong EtOHJ+B increase (+99% vs. low SM). Late harvest enhanced DW and EtOHJ+B (+107% vs. early harvest), despite decreasing extractives and increasing structural fiber components. Water use efficiency of EtOHJ+B improved with high vs. low SM, although differences faded in late harvest. Upscale of EtOHJ+B and WUE data indicated a range of 21,000–82,000 ha of sorghum cultivation and 60–117 Mm3 of irrigation water, as amounts of resources needed to supply an 85,000 m3·yr−1 bio-ethanol plant. This large variation in land and water needs depended on specific combinations between crop factors SM and harvests.