This study introduces a general negative pressure annealing strategy to fabricate ultra-high-loading single-atom catalysts (SACs) with metal contents up to 27.3–44.8 wt% for 13 different metals on a typical carbon nitride (PCN) matrix. The approach also enables the synthesis of high-entropy single-atom catalysts (HESACs) with multiple metal single atoms and high metal contents. In-situ aberration-corrected HAADF-STEM and ex-situ X-ray absorption fine structure (XAFS) techniques demonstrate that the negative pressure annealing treatment accelerates the removal of anionic ligands in metal precursors and enhances the bonding of metal species with nitrogen-deficient sites, leading to the formation of dense N-coordinated metal sites. The Pt SACs/PCN catalysts exhibit significantly enhanced activity in propane oxidation towards liquid products, including acetone, methanol, and acetic acid. This work presents a straightforward and universal method for achieving low-cost, high-density SACs with efficient catalytic transformations, which is crucial for improving the industrial prospects of heterogeneous single-atom catalysts (SACs).This study introduces a general negative pressure annealing strategy to fabricate ultra-high-loading single-atom catalysts (SACs) with metal contents up to 27.3–44.8 wt% for 13 different metals on a typical carbon nitride (PCN) matrix. The approach also enables the synthesis of high-entropy single-atom catalysts (HESACs) with multiple metal single atoms and high metal contents. In-situ aberration-corrected HAADF-STEM and ex-situ X-ray absorption fine structure (XAFS) techniques demonstrate that the negative pressure annealing treatment accelerates the removal of anionic ligands in metal precursors and enhances the bonding of metal species with nitrogen-deficient sites, leading to the formation of dense N-coordinated metal sites. The Pt SACs/PCN catalysts exhibit significantly enhanced activity in propane oxidation towards liquid products, including acetone, methanol, and acetic acid. This work presents a straightforward and universal method for achieving low-cost, high-density SACs with efficient catalytic transformations, which is crucial for improving the industrial prospects of heterogeneous single-atom catalysts (SACs).