Globally, there are 2 billion ‘informal’ workers, who lack access to social protection while facing profound health risks and socioeconomic exclusions. The informal economy has generated most jobs in Low and Middle-Income Countries (LMICs), but few studies have explored informal workers' complex health vulnerabilities, including in the face of climate change. This paper will discuss recent action-research in Indore (India), Harare, and Masvingo (Zimbabwe) with informal workers like vendors, waste-pickers, and urban farmers. We conducted qualitative interviews (N = 110 in India), focus group discussions (N = 207 in Zimbabwe), and a quantitative survey (N = 418 in Zimbabwe). Many informal workers live in informal settlements (‘slums’), and we highlight the interrelated health risks at their homes and workplaces. We explore how climate-related threats—including heatwaves, drought, and floods—negatively affect informal workers' health and livelihoods. These challenges often have gender-inequitable impacts. We also analyse workers' individual and collective responses. We propose a comprehensive framework to reveal the drivers of health in the informal economy, and we complement this holistic approach with a new research agenda. Our framework highlights the socioeconomic, environmental, and political determinants of informal workers' health. We argue that informal workers may face difficult trade-offs, due to competing priorities in the face of climate change and other risks. Future interventions will need to recognise informal workers’ array of risks and co-develop multifaceted solutions, thereby helping to avoid such impossible choices. We recommend holistic initiatives to foster health and climate resilience, as well as participatory action-research partnerships and qualitative, intersectional data-collection with informal workers. •Climate change is exacerbating many risks to informal workers' health and livelihoods.•WASH access may foster gender equality and decent work, while tackling heat stress.•Policymakers can partner with informal workers to create inclusive, multi-pronged interventions.