Developing an anti-infective shape-memory hemostatic sponge with ability of guiding in situ tissue regeneration for noncompressible hemorrhage in civilian and battlefield settings remains a challenge. Here, hemostatic chitosan sponge with highly interconnective microchannels was engineered by combining 3D printed fiber leaching and freeze-drying methods and then modified with hydrophobic alkyl chains. The microchannelled alkylated chitosan sponge (MACS) exhibited a strong capacity for water/blood absorption and rapid shape recovery. Compared to clinically used gauze, gelatin sponge, CELOX, and CELOX-gauze, the MACS demonstrated higher pro-coagulant and hemostatic capacities in lethally normal/heparinized rat and pig liver perforation models. Also, it exhibited strong anti-infective activity against S. aureus and E. coli. Additionally, it promoted liver parenchymal cell infiltration, vascularization, and tissue integration in a rat liver defect model. Overall, the MACS demonstrated promising clinical translational potential in cost effectively treating lethal noncompressible hemorrhage and in facilitating wound healing.