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Background Air pollution exposure has been linked to ischaemic stroke (IS), yet the sensitive life stages for pollution-related IS risk and the interplay of genetic susceptibility remain unclear.Methods We analysed 404 234 IS-free participants from a large UK prospective cohort. Exposures to PM 2.5, SO2 and O3 were estimated across five life stages (toddlerhood, childhood, adolescence, youth and middle-aged to older adulthood) and cumulatively from birth. Bayesian life-course models identified sensitive exposure windows and quantile g-computation estimated mixture effects. Gene–environment interactions with polygenic risk scores (PRSs) were evaluated using relative excess risk due to interaction (RERI), attributable proportion (AP) and synergy index (S).Results During a median follow-up of 13.6 years, 8130 IS cases occurred. Associations between air pollutants and IS varied by life stage, with stronger associations observed in middle-aged to older adulthood (HRs: 1.586 (95% CI 1.554 to 1.618) for PM 2.5, 1.180 (1.167–1.193) for SO2, 1.588 (1.552–1.624) for O3). For cumulative exposures, elevated risks were seen from toddlerhood to older adulthood (HRs: 1.139–1.313). Mixture effects were most pronounced in toddlerhood (HR=2.829, 95% CI 2.623 to 3.052), largely driven by SO2 (weight=0.500). Bayesian life-course models suggested PM2.5 (25.2%) and O3 (24.5%) had greater relative contributions in childhood and adolescence whereas SO2 (45.9%) contributed more in later life. Higher pollutant exposure and elevated PRS were associated with higher IS risk (RERI>0, AP>0 and S>1).Conclusions Air pollution associations with IS risk vary across life stages and may be influenced by genetic susceptibility, supporting a life-course prevention approach.