Al-Khiday, located on the bank of the White Nile in Sudan, offers an exceptionally preserved stratigraphic sequence, providing a unique opportunity to use organic residue analysis to investigate diet and subsistence during the Khartoum Mesolithic and the Early Neolithic, a period of nearly 3500 years (7000–4500 cal BC). While the vast and diverse Mesolithic fish assemblage indicates a strong reliance on products from aquatic habitats, floodplains, vegetated marshes, and open water, results from the lipid residue analysis suggest that the fish were not cooked in ceramic pots, but consumed in other ways. Rather, pots were more specialized in processing plants, including wild grasses, leafy plants, and sedges. These results, confirmed by experimental analysis, provide, for the first time, direct chemical evidence for plant exploitation in the Khartoum Mesolithic. Non-ruminant fauna (e.g., warthog) and low lipid-yielding reptiles (e.g., Adanson’s mud turtle and Nile monitor lizard), found in significant numbers at al-Khiday, were likely also cooked in pots. There is little evidence for the processing of wild ruminants in the Mesolithic pots, suggesting either that ruminant species were not routinely hunted or that large wild fauna may have been cooked in different ways, possibly grilled over fires. These data suggest sophisticated economic strategies by sedentary people exploiting their ecological niche to the fullest. Pottery use changed considerably in the Early Neolithic, with ruminant products being more routinely processed in pots, and while the exploitation of domesticates cannot be confirmed by a small faunal assemblage, some dairying took place. The results provide valuable information on Early and Middle Holocene lifeways in central Sudan.