Runners on average do not have a high risk of developing knee osteoarthritis, even though running places very high loads on the knee joint. Here we used gait analysis, musculoskeletal modeling, and a discrete-element model of knee contact mechanics to estimate strains of the medial knee cartilage in walking and running in 22 young adults (age 23 ± 3 years). A phenomenological model of cartilage damage, repair, and adaptation in response to these strains then estimated the failure probability of the medial knee cartilage over an adult lifespan (age 23–83 years) for 6 km/day of walking vs. walking and running 3 km/day each. With no running, by age 55 the cumulative probability of medial knee cartilage failure averaged 36% without repair and 13% with repair, similar to reports on incidence of knee osteoarthritis in non-obese adults with no knee injuries, but the probability for running was very high without repair or adaptation (98%) and remained high after including repair (95%). Adaptation of the cartilage compressive modulus, cartilage thickness, and the tibiofemoral bone congruence in response to running (+1.15 standard deviations of their baseline values) was necessary for the failure probability of walking and running 3 km/day each to equal the failure probability of walking 6 km/day. The model results suggest two conclusions for further testing: (i) unlike previous findings on the load per unit distance, damage per unit distance on the medial knee cartilage is greater in running vs. walking, refuting the “cumulative load” hypothesis for long-term joint health; (ii) medial knee cartilage is unlikely to withstand a lifetime of mechanical loading from running without a natural adaptation process, supporting the “cartilage conditioning” hypothesis for long-term joint health.