Natural emissions (vegetation, soil, and lightning) are the dominant sources of non-methane biogenic volatile organic compounds (BVOCs) and nitrogen oxides (NOx≡ NO + NO2) released into the atmosphere over Africa. BVOCs and NOx interact with each other and strongly impact their own chemical lifetimes and degradation pathways, in particular through their influence on hydroxyl radical levels. To account for this intricate interplay between NOx and VOCs, we design and apply a novel inversion setup aiming at simultaneous optimization of monthly VOC and NOx emissions in 2019 in a regional chemistry-transport model, based on Tropospheric Ozone Monitoring Instrument (TROPOMI) HCHO and NO2 satellite observations. The TROPOMI-based inversions suggest substantial underestimations of natural NOx and VOC emissions used as a priori in the model. The annual flux over Africa increases from 125 to 165 Tg yr−1 for isoprene, from 1.9 to 2.4 TgN yr−1 for soil NO emissions, and from 0.5 to 2.0 TgN yr−1 for lightning NO emissions. Despite the NOx emission increase, evaluation against in situ NO2 measurements at seven rural sites in western Africa displays significant model underestimations after optimization. The large increases in lightning emissions are supported by comparisons with TROPOMI cloud-sliced upper-tropospheric NO2 volume mixing ratios, which remain underestimated by the model even after optimization. Our study strongly supports the application of a bias correction to the TROPOMI HCHO data and the use of a two-species constraint (vs. single-species inversion), based on comparisons with isoprene columns retrieved from the Cross-track Infrared Sensor (CrIS).