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Aircraft wastewater surveillance has been proposed as a new approach to monitor the global spread of pathogens. Here we develop a computational framework providing actionable information for the design and estimation of the effectiveness of global aircraft-based wastewater surveillance networks (WWSNs). We study respiratory diseases of varying transmission potential and find that networks of 10–20 strategically placed wastewater sentinel sites can provide timely situational awareness and function effectively as an early warning system. The model identifies potential blind spots and suggests optimization strategies to increase WWSN effectiveness while minimizing resource use. Our findings indicate that increasing the number of sentinel sites beyond a critical threshold does not proportionately improve WWSN capabilities, emphasizing the importance of resource optimization. We show, through retrospective analyses, that WWSNs can notably shorten detection time for emerging pathogens. The approach presented offers a realistic analytic framework for the analysis of WWSNs at airports.