Atmospheric vapor pressure deficit (VPD) is a key climatic factor that influences vegetation productivity and the global carbon cycle. With ongoing climate warming, VPD has been rising globally. However, the effects of this increase on gross primary production (GPP), especially under different driving mechanisms, remain unclear. This uncertainty limits our ability to predict terrestrial ecosystem responses. In this study, we examined the spatial heterogeneity and climatic drivers of VPD impacts on GPP using three global datasets—FLUXCOM GPP, GOSIF GPP, and VPM GPP—from 2000 to 2018. We classified VPD increases into three types: temperature-driven, combined temperature and relative humidity-driven, and relative humidity-driven. Using trend analysis, partial correlation, ridge regression, and random forest models, we identified a distinct latitudinal gradient in VPD-GPP relationships, presenting an “N-shaped” pattern. VPD positively influenced GPP near the equator and at high latitudes, but showed predominantly negative effects in mid-latitudes. This spatial variation was shaped by the background climate conditions and the interaction of water and energy-related factors. In regions where temperature and humidity changed synchronously, VPD effects on GPP were often neutral or positive. In contrast, asynchronous changes—particularly those dominated by humidity declines—tended to intensify negative impacts. Our findings highlight the diverse vegetation responses to different drivers of VPD increase. They also emphasize the importance of correctly representing regional VPD heterogeneity in ecosystem modeling and future carbon cycle projections.