Pesticides can be transported into estuaries via spray drift, ground water contamination and surface runoff. Increasing climatic variability and global pesticide use are likely to increase the exposure of harvested estuarine species, and therefore seafood consumers, to agrichemicals. Post-harvest processing strategies present opportunities to reduce pesticide residues in seafood and so mitigate consumer health risks. We evaluated the efficacies of thermal processing (cooking) and depuration (holding individuals in clean flow-through seawater) for reducing pesticide residues in wild-caught giant mud crab (Scylla serrata) edible tissues (flesh and brown meat (i.e. hepatopancreas and gonads)). Pesticide residues were detected in 82% of assessed crabs, with five analytes quantified (cyprodinil, diuron, imidacloprid, propargite and triazophos). Correlative analyses revealed cooking at ~82°C for 2 min 100-g–1 body mass reduced all pesticide concentrations (and the total residues) by 7–99%—except for cyprodinil (51% increase)—although changes were highly variable among tissues. Imidacloprid was the only residue detected in crabs held for depuration, which was effectively reduced (by 81%) after six days, with complete elimination in 95% of individuals after 12 days. However, peaks in imidacloprid concentrations were recorded up to six days post-collection for some individuals, which is an important consideration for food safety monitoring and depuration duration. A human health risk assessment identified that the concentrations of pesticide residues in crab tissues posed no negative health effects to seafood consumers, particularly following depuration and thermal processing. While the data support post-harvest processing methods for reducing pesticide residues in giant mud crab tissues, processing recommendations require defined maximum residue limits for Australian seafood, with consideration of consumption preferences.