BACKGROUND: Drought is an understudied driver of infectious disease dynamics. Amidst the ongoing southwestern North American megadrought, California (USA) is having the driest multi-decadal period since 800 CE, exacerbated by anthropogenic warming. In this study, we aimed to examine the influence of drought on coccidioidomycosis, an emerging infectious disease in southwestern USA. METHODS: We analysed California census tract-level surveillance data from 2000 to 2020 using generalised additive models and distributed monthly lags on precipitation and temperature. We then developed an ensemble prediction algorithm of incident cases of coccidioidomycosis per census tract to estimate the counterfactual incidence that would have occurred in the absence of drought. FINDINGS: Between April 1, 2000, and March 31, 2020, there were 81 448 reported cases of coccidioidomycosis throughout California. An estimated 1467 excess cases of coccidioidomycosis were observed in California in the 2 years following the drought that occurred between 2007 and 2009, and an excess 2649 drought-attributable cases of coccidioidomycosis were observed in the 2 years following the drought that occurred between 2012 and 2015. These increased numbers of cases more than offset the declines in cases that occurred during drought. An IQR increase in summer temperatures was associated with 2·02 (95% CI 1·84-2·22) times higher incidence in the following autumn (September to November), and an IQR increase in precipitation in the winter was associated with 1·45 (1·36-1·55) times higher incidence in the autumn. The effect of winter precipitation was 36% (25-48) stronger when preceded by two dry, rather than average, winters. Incidence in arid counties was most sensitive to precipitation fluctuations, while incidence in wetter counties was most sensitive to temperature. INTERPRETATION: In California, multi-year cycles of dry conditions followed by a wet winter increases transmission of coccidioidomycosis, especially in historically wetter areas. With anticipated increasing frequency of drought in southwestern USA, continued expansion of coccidioidomycosis, along with more intense seasons, is expected. Our results motivate the need for heightened precautions against coccidioidomycosis in seasons that follow major droughts. FUNDING: National Institutes of Health.