A general negative pressure annealing approach is introduced to fabricate ultra-high-loading single-atom catalyst (SAC) libraries with metal contents up to 27.3–44.8 wt% for 13 different metals on a carbon nitride matrix. This method enables the synthesis of high-entropy SACs (HESACs) with multiple metal single atoms and high metal content. In-situ aberration-corrected HAADF-STEM and ex-situ XAFS show that negative pressure annealing accelerates the removal of anionic ligands in metal precursors and enhances bonding with nitrogen-defective sites, forming dense N-coordinated metal sites. Increasing platinum (Pt) SAC loading to 41.8 wt% significantly enhances propane oxidation activity towards liquid products like acetone, methanol, and acetic acid. The approach provides a straightforward and universal method for creating low-cost, high-density SACs for efficient catalytic transformations. The study highlights the importance of high metal loading and sufficient areal density for SACs, which are challenging to achieve. The negative pressure annealing strategy is shown to be effective in suppressing metal aggregation and promoting N-coordinated single-atom sites. The method is applicable to various transition metals and N-doped carbon substrates, enabling the preparation of SACs with high metal loading and areal density. The Pt SACs/PCN exhibit excellent catalytic performance in propane oxidation, with high activity and stability after multiple reuse cycles. The work demonstrates the potential of SACs in sustainable chemistry and efficient catalytic transformations.A general negative pressure annealing approach is introduced to fabricate ultra-high-loading single-atom catalyst (SAC) libraries with metal contents up to 27.3–44.8 wt% for 13 different metals on a carbon nitride matrix. This method enables the synthesis of high-entropy SACs (HESACs) with multiple metal single atoms and high metal content. In-situ aberration-corrected HAADF-STEM and ex-situ XAFS show that negative pressure annealing accelerates the removal of anionic ligands in metal precursors and enhances bonding with nitrogen-defective sites, forming dense N-coordinated metal sites. Increasing platinum (Pt) SAC loading to 41.8 wt% significantly enhances propane oxidation activity towards liquid products like acetone, methanol, and acetic acid. The approach provides a straightforward and universal method for creating low-cost, high-density SACs for efficient catalytic transformations. The study highlights the importance of high metal loading and sufficient areal density for SACs, which are challenging to achieve. The negative pressure annealing strategy is shown to be effective in suppressing metal aggregation and promoting N-coordinated single-atom sites. The method is applicable to various transition metals and N-doped carbon substrates, enabling the preparation of SACs with high metal loading and areal density. The Pt SACs/PCN exhibit excellent catalytic performance in propane oxidation, with high activity and stability after multiple reuse cycles. The work demonstrates the potential of SACs in sustainable chemistry and efficient catalytic transformations.