Cartilage and joint damage easily degenerates cartilage and turns into osteoarthritis (OA), which seriously affects human life and work, and has no cure currently. The temporal and spatial changes of multiple microenvironments upon the damage of cartilage and joint are noticed, including the emergences of inflammation, bone remodeling, blood vessels, and nerves, as well as alterations of extracellular and pericellular matrix, oxygen tension, biomechanics, underneath articular cartilage tissues, and pH value. This review summarizes the existing literatures on microenvironmental changes, mechanisms, and their negative effects on cartilage regeneration following cartilage and joint damage. We conclude that time-dependently rebuilding the multiple normal microenvironments of damaged cartilage is the key for cartilage regeneration after systematic studies for the timing and correlations of various microenvironment changes.