ABSTRACT Smoke impacts from large wildfires are mounting, and the projection is for more such events in the future as the one experienced October 2017 in Northern California, and subsequently in 2018 and 2020. Further, the evidence is growing about the health impacts from these events which are also difficult to simulate. Therefore, we simulated air quality conditions using a suite of remotely-sensed data, surface observational data, chemical transport modeling with WRF-CMAQ, one data fusion, and three machine learning methods to arrive at datasets useful to air quality and health impact analyses. To demonstrate these analyses, we estimated the health impacts from smoke impacts during wildfires in October 8–20, 2017, in Northern California, when over 7 million people were exposed to Unhealthy to Very Unhealthy air quality conditions. We investigated using the 5-min available GOES-16 fire detection data to simulate timing of fire activity to allocate emissions hourly for the WRF-CMAQ system. Interestingly, this approach did not necessarily improve overall results, however it was key to simulating the initial 12-hr explosive fire activity and smoke impacts. To improve these results, we applied one data fusion and three machine learning algorithms. We also had a unique opportunity to evaluate results with temporary monitors deployed specifically for wildfires, and performance was markedly different. For example, at the permanent monitoring locations, the WRF-CMAQ simulations had a Pearson correlation of 0.65, and the data fusion approach improved this (Pearson correlation = 0.95), while at the temporary monitor locations across all cases, the best Pearson correlation was 0.5. Overall, WRF-CMAQ simulations were biased high and the geostatistical methods were biased low. Finally, we applied the optimized PM2.5 exposure estimate in an exposure-response function. Estimated mortality attributable to PM2.5 exposure during the smoke episode was 83 (95% CI: 0, 196) with 47% attributable to wildland fire smoke. Implications: Large wildfires in the United States and in particular California are becoming increasingly common. Associated with these large wildfires are air quality and health impact to millions of people from the smoke. We simulated air quality conditions using a suite of remotely-sensed data, surface observational data, chemical transport modeling, one data fusion, and three machine learning methods to arrive at datasets useful to air quality and health impact analyses from the October 2017 Northern California wildfires. Temporary monitors deployed for the wildfires provided an important model evaluation dataset. Total estimated regional mortality attributable to PM2.5 exposure during the smoke episode was 83 (95% confidence interval: 0, 196) with 47% of these deaths attributable to the wildland fire smoke. This illustrates the profound effect that even a 12-day exposure to wildland fire smoke can have on human health.