Musculoskeletal pain is driven by degenerative conditions such as osteoarthritis or intervertebral disk degeneration. This creates a major burden on health systems and patient quality of life. Platelet-rich plasma (PRP) is an orthobiologic that contains platelets and growth factors which promote angiogenesis, modulate inflammation, and support tissue repair. Mechanobiology is central in the healing process, where mechanical loading regulates cellular behavior through mechanotransduction pathways including integrin/FAK and RhoA/ROCK. This use of signaling pathways allows for regeneration along multiple different tissue types. Evidence suggests that PRP and mechanical loading may act together to promote tissue repair, with PRP-derived signals interacting with biomechanical cues to enhance fibroblast activation, remodeling, and regenerative responses. There is variability in PRP preparation, rehabilitation protocols, and tissue-specific responses, which all highlight the need for a more standardized and guided treatment strategy. Understanding the interplay between PRP-derived biologic signaling and mechanobiologic pathways may help inform the development of more standardized, tissue-specific regenerative treatment strategies and could potentially contribute to improved clinical outcomes in patients with musculoskeletal pain.