Solar-induced fluorescence (SIF) shows enormous promise as a proxy for photosynthesis and as a tool for modeling variability in gross primary productivity (GPP) and net biosphere exchange (NBE). In this study, we explore the skill of SIF and other vegetation indicators in predicting variability in global atmospheric CO2 observations, and thus global variability in NBE. We do so using a four-year record of global CO2 observations from NASA’s Orbiting Carbon Observatory 2 (OCO-2) satellite and using a geostatistical inverse model. We find that existing SIF products closely correlate with space-time variability in atmospheric CO2 observations in the extra-tropics but show weaker explanatory power across the tropics. In the extra-tropics, all SIF products exhibit greater skill in explaining variability in atmospheric CO2 observations compared to an ensemble of process-based CO2 flux models and other vegetation indicators. Furthermore, we find that using SIF as a predictor variable in the geosatistical inverse model shifts the seasonal cycle of estimated NBE and yields an earlier end to the growing season relative to other vegetation indicators. In tropical biomes, by contrast, the seasonal cycles of SIF products and estimated NBE are out of phase, and existing respiration and biomass burning estimates do not reconcile this discrepancy. Overall, our results highlight several advantages and challenges of using SIF products to help predict global variability in GPP and NBE.