Tissue-level mechanics (e.g., stress and strain) are important factors governing tissue remodeling and development of knee osteoarthritis (KOA), and hence, the success of physical rehabilitation. To date, no clinically feasible analysis toolbox has been introduced and used to inform clinical decision making with subject-specific in-depth joint mechanics of different activities. Herein, we utilized a rapid state-of-the-art electromyography-assisted musculoskeletal finite element analysis toolbox with fibril-reinforced poro(visco)elastic cartilages and menisci to investigate knee mechanics in different activities. Tissue mechanical responses, believed to govern collagen damage, cell death, and fixed charge density loss of proteoglycans, were characterized within 15 patients with KOA while various daily activities and rehabilitation exercises were performed. Results showed more inter-participant variation in joint mechanics during rehabilitation exercises compared to daily activities. Accordingly, the devised workflow may be used for designing subject-specific rehabilitation protocols. Further, results showed the potential to tailor rehabilitation exercises, or assess capacity for daily activity modifications, to optimally load knee tissue, especially when mechanically-induced cartilage degeneration and adaptation are of interest.