Hydrogels exhibit promising applications, particularly due to their high water content and excellent biocompatibility. Despite notable progress in hydrogel technology, the concurrent enhancement of water content, mechanical strength, and low friction poses substantial challenges to practical utilization. In this study, employing molecular and network design guided based on multiple synergistic enhancement mechanisms, we have developed a robust polyvinyl alcohol (PVA)–polyacrylic acid (PAA)–polyacrylamide (PAAm) three-network (TN) hydrogel exhibiting high water content, enhanced strength, low friction, and fatigue resistance. The hydrogel manifests a water content of 63.7%, compression strength of 6.3 MPa, compression modulus of 2.68 MPa, tensile strength reaching 7.3 MPa, and a tensile modulus of 10.27 MPa. Remarkably, even after one million cycles of dynamic loading, the hydrogel exhibits no signs of fatigue failure, with a minimal strain difference of only 1.15%. Furthermore, it boasts a low sliding coefficient of friction (COF) of 0.043 and excellent biocompatibility. This advancement extends the applications of hydrogels in emerging fields within biomedicine and soft bio-devices, including load-bearing artificial tissues, artificial blood vessels, tissue scaffolds, robust hydrogel coatings for medical devices, and joint parts of soft robots.