Osteoarthritis (OA) is one of the most common joint diseases currently, characterized by the gradual degradation of cartilage, remodeling of subchondral bone, development of synovitis, degenerative alterations in the menisci, and formation of osteophytes. Generally, loss of articular cartilage is the most common pathological manifestation of OA. However, owing to the lack of blood vessels and nerves, the damaged cartilage is unable to execute self-repair. Therefore, early detection and treatment of cartilage lesions are extremely vital. Given that precise diagnosis and therapeutic strategy are indispensable from the basic pathological features of OA, an ideal therapeutic strategy should cater to the specific features of the OA microenvironment to achieve disease-modifying therapy. To date, nanomedicine presents an opportunity to achieve the precisely targeted delivery of agents and stimuli-sensitive release at the optimum dose, which may be coupled with a controlled release profile and reduced side effects. This review mainly summarizes inherent and microenvironment traits of OA and outlines stimuli-responsive nanotherapies, including internal bio-responsive (e.g., reactive oxygen species, pH, and protease) and external (e.g., photo stimuli, temperature, ultrasound, and magnetic field) responsive nanotherapies. Furthermore, multi-targeted therapeutic strategies combined with multi-modality imaging are also discussed. In general, future exploration of more novel stimuli-responsive nanotherapies that can be used for early diagnosis and cartilage targeting may help ameliorate OA-related cartilage damage, decrease pain, and promote joint function.