Musculoskeletal pain and inflammation can vary from localised pain like pain in the shoulders and neck to widespread pain like fibromyalgia, and as per estimates, around 90% of humans have experienced such pain. Oral non-steroidal anti-inflammatory drugs (NSAIDs) are frequently prescribed for such conditions but are associated with concerns like gastric irritation and bleeding. In the present study, a microemulsion-based gel comprising β-caryophyllene, isopropyl myristate, Tween 80, and normal saline was prepared as a topical option for managing topical pain and inflammation. The globules of the microemulsion were below 100 nm with a zetapotential of around -10 mV. The drug entrapment was >87% with a drug loading of >23%. The permeation studies established better skin permeation (20.11 ± 0.96 μg cm h) and retention of the drug (4.96 ± 0.02%) from the developed system vis-à-vis the conventional product (9.73 ± 0.35 μg cm h; 1.03 ± 0.01%). The dermatokinetic studies established the better pharmacokinetic profile of the bioactive in the epidermis and dermis layers of the skin. The anti-inflammatory potential in carrageenan-induced rat paw oedema was more pronounced than the conventional product (~91% vis-à-vis ~77%), indicating a better pharmacodynamic outcome from the developed system. The nanotechnology-based natural bioactive product with improved efficacy and drug loading can provide a better alternative for the management of musculoskeletal pain.