Gait modification is a common nonsurgical approach to alter the mediolateral distribution of knee contact forces, intending to decelerate or postpone the progression of mechanically-induced knee osteoarthritis (KOA). Nevertheless, the success rate of these approaches is controversial, with no studies conducted to assess alterations in tissue-level knee mechanics governing cartilage degradation response in KOA patients undertaking gait modifications. Thus, here we investigated the effect of different conventional gait conditions and modifications on tissue-level knee mechanics previously suggested as indicators of collagen network damage, cell death, and loss of proteoglycans in knee cartilage. Five participants with medial KOA were recruited, and musculoskeletal finite element analyses were conducted to estimate subject-specific tissue mechanics of knee cartilages during two gait conditions (i.e., barefoot and shod) and six gait modifications (i.e., 0°, 5°, and 10° lateral wedge insoles, toe-in, toe-out, and wide stance). Based on our results, the optimal gait modification varied across the participants. Overall, toe-in, toe-out, and wide stance showed the greatest reduction in tissue mechanics within medial tibial and femoral cartilages. Gait modifications could effectually alter maximum principal stress (~20±7 %) and shear strain (~9±4 %) within the medial tibial cartilage. Nevertheless, lateral wedge insoles did not reduce joint- and tissue-level mechanics considerably. Significance: This proof-of-concept study emphasizes the importance of the personalized design of gait modifications to account for biomechanical risk factors associated with cartilage degradation. This article is protected by copyright. All rights reserved.