Knee osteoarthritis (KOA), a degenerative joint disease driven by biomechanical instability, involves cartilage degradation, muscle dysfunction, and MLK3/P38 MAPK pathway activation. Histone deacetylase 4 (HDAC4), a regulator of chondrocyte and muscle homeostasis, interacts with this pathway during disease progression. While Hyriopsis Bioactive Polysaccharide-Anodonta (HBP-A) exhibits P38 MAPK inhibitory properties in vitro, its in vivo therapeutic effects on musculoskeletal tissues remain uncharacterised. A destabilisation of the medial meniscus (DMM) mouse model was established to investigate HBP-A's therapeutic potential. Animals were randomly divided into sham-operated, DMM-induced, and HBP-A-treated groups. Following surgical induction, HBP-A (0.26 g/kg) was administered daily via oral gavage for 4 weeks. Comprehensive assessments included behavioural tests for pain sensitivity, micro-CT scanning, histological evaluation, and transmission electron microscope. Molecular mechanisms were investigated via immunohistochemical or immunofluorescence staining of MLK3, P38 MAPK, Caspase-3, and HDAC4, complemented by RT-qPCR analysis of myokine expression. HBP-A treatment significantly alleviated pain sensitivity compared to the DMM group. Structural evaluations revealed preserved subchondral bone integrity and attenuated cartilage degeneration, with histological scoring confirming reduced pathological changes. Quadriceps exhibited mitigated atrophy and restored ultrastructural organisation. Molecular profiling demonstrated suppressed MLK3/P38 MAPK pathway activation, diminished apoptotic activity, and elevated HDAC4 expression in both cartilage and quadriceps. HBP-A additionally normalised dysregulated expression of muscle-derived osteogenic factors linked to bone-cartilage crosstalk. These findings establish HBP-A as a dual-target therapeutic agent for KOA, concurrently mitigating cartilage and muscle degeneration through MLK3/P38 MAPK/HDAC4 axis modulation.