Leaf senescence is essential for the nutrient economy of crops and is executed by so-called senescence-associated genes (SAGs). Here we explored the monocot C₄ model crop Sorghum bicolor for a holistic picture of SAG profiles by RNA-seq. Leaf samples were collected at four stages during developmental senescence, and in total, 3396 SAGs were identified, predominantly enriched in GO categories of metabolic processes and catalytic activities. These genes were enriched in 13 KEGG pathways, wherein flavonoid and phenylpropanoid biosynthesis and phenylalanine metabolism were overrepresented. Seven regions on Chromosomes 1, 4, 5 and 7 contained SAG ‘hotspots’ of duplicated genes or members of cupin superfamily involved in manganese ion binding and nutrient reservoir activity. Forty-eight expression clusters were identified, and the candidate orthologues of the known important senescence transcription factors such as ORE1, EIN3 and WRKY53 showed “SAG” expression patterns, implicating their possible roles in regulating sorghum leaf senescence. Comparison of developmental senescence with salt- and dark- induced senescence allowed for the identification of 507 common SAGs, 1996 developmental specific SAGs as well as 176 potential markers for monitoring senescence in sorghum. Taken together, these data provide valuable resources for comparative genomics analyses of leaf senescence and potential targets for the manipulation of genetic improvement of Sorghum bicolor.