Growing varieties with higher water-use efficiency is crucial to address water limitation in agriculture. Breeding programs often resort to model plants, and Setaria viridis has been consolidating its position as a model for C4 grasses. However, we lack a detailed analysis of drought-induced metabolic changes in S. viridis. To partially redress this, we assessed the primary metabolic profile of roots, leaves, and panicles in response to three watering levels. Five-day-old seedlings were submitted to water-limiting conditions for 25 days when samples were harvested. GC-MS-based analysis revealed that each plant organ had a specific metabolic profile, with TCA intermediates altered in above- and underground parts. The sPLS-DA analysis allowed clear separation of the water regimes for the three organs. Of the 36 most important metabolites, only four (sucrose, glycerol-3P, gluconate and adenine) were shared by all plant organs. A subset of 12 metabolites, including proline, were further evaluated as drought bioindicator candidates, with galactinol and gluconate emerging for vegetative parts while alanine seems informative of aerial part water status. In general, water limitation decreased the content of nitrogen compounds in aboveground tissues and increased the amounts of carbohydrates, especially in the sink organs. This study adds to our understanding of the metabolic responses of grasses to water limitation and identified potential bioindicators for drought in different plant organs.