Articular cartilage enables nearly frictionless joint motion by regulating how interstitial fluid pressurizes and supports mechanical loads. Loss of this function is a key contributor to osteoarthritis, yet the mechanisms linking tissue composition, fluid pressurization, and lubrication remain poorly understood. Here we combine tribological testing of healthy and enzymatically degraded bovine cartilage with sample-specific finite element (FE) modeling to investigate how interstitial fluid load support (IFLS) governs the coefficient of friction (COF). While direct measurement of IFLS is technically demanding, our FE-based approach enables empirical estimation of IFLS. Cartilage plugs were articulated against each other under creep loading and lubricated with either synovial fluid or saline. The finite element model enabled empirical quantification of IFLS during testing, which we validated against previously reported experimental data. We observed that once interstitial fluid load support declined to low levels, lubrication became increasingly dependent on the external medium. While the strain–IFLS relationship remained linear across all conditions, degeneration disrupted the otherwise consistent IFLS–COF relationship. These findings help clarify how fluid pressurization and tissue integrity jointly regulate cartilage lubrication, providing a functional framework for evaluating cartilage repair strategies and extending to other biphasic materials such as hydrogels and engineered tissues.