Global climate zones are experiencing widespread shifts with ongoing rise in atmospheric CO2, influencing vegetation growth and shifting its distributions to challenge ecosystem structure and function, posing threats on ecological and societal safety. However, how rising atmospheric CO2 affects the pace of global climate zone shifts is highly uncertain. More attentions are urgently required to understand the underlying mechanisms and quantifications of regional climate vulnerability in response to rising CO2. In this study, we employ nine Earth system models from CMIP6 to investigate global climate zone shifts with rising CO2, unravel the effects of vegetation physiological response (PHY), and categorize climate vulnerable regions depending on the extent of climate zone shifts. We find that climate zone shifts over half of the global land area, 16.8% of which is contributed by PHY at 4 × CO2. Intriguingly, besides warming, PHY-induced precipitation changes and their interactions with warming dominate about two-fifths of PHY-forced shifts, providing potential direction for model improvement in future predictions of climate zone shifts. Aided with PHY effects, 4 × CO2 imposes substantial climate zone shifts over about one-fifth of the global land area, suggesting substantial changes in local climate and ecosystem structure and functions. Hence, those regions would experience strong climate vulnerability, and face high risk of climate extremes, water scarcity and food production. Our results quantitatively identify the vulnerable regions and unravel the underlying drivers, providing scientific insights to prioritize conservation and restoration efforts to ensure ecological and social safety globally.