Mesozooplankton are a crucial link between primary producers and higher trophic levels and play a vital role in marine food webs, biological carbon pumps, and sustaining fishery resources. However, the global distribution of mesozooplankton biomass and the relevant controlling mechanisms remain elusive. We compared four machine learning algorithms (Boosted Regression Trees, Random Forest, Artificial Neural Network, and Support Vector Machine) to model the spatiotemporal distributions of global mesozooplankton biomass. These algorithms were trained on a compiled dataset of published mesozooplankton biomass observations with corresponding environmental predictors from contemporaneous satellite observations (temperature, chlorophyll, salinity, and mixed layer depth). We found that Random Forest achieved the best predictive accuracy with R2 and RMSE (Root Mean Standard Error) of 0.57 and 0.39, respectively. Also, the global distribution of mesozooplankton biomass predicted by the Random Forest model was more consistent with the observational data than other models. We used the Random Forest model to create a global map of mesozooplankton biomass which serves as a reference for validating process-based ecosystem models. The model outputs confirm that environmental factors, especially surface Chl a, a proxy for prey availability, significantly correlate with the spatiotemporal distribution of mesozooplankton biomass. The scaling relationship between the mesozooplankton biomass and Chl a can be used as an emergent constraint for model validation and development. Moreover, our model predicts that the global mesozooplankton biomass will decrease by 3% by the end of this century under the “business-as-usual” scenarios, potentially reducing fishery production and carbon sequestration. Our study contributes to predicting global mesozooplankton biomass and provides deep insights into the underlying environmental impacts on the distribution of mesozooplankton biomass.