To determine the efficacy of transdermal anti-inflammatory patches in the treatment of acute and chronic musculoskeletal pain. A comprehensive search of: Cochrane Central register of controlled trials, EMBASE, MEDLINE, CINAHL and PubMed, for studies using transdermal anti-inflammatory patches vs placebo for management of musculoskeletal pain, e.g. soft tissue injuries or tendonitis (last search January 2024). Cochrane Risk of Bias Tools v1 was used for quality assessment and GRADE determined certainty of evidence. Meta-analysis was performed. Twenty-three randomized placebo-controlled trials (n = 4729) were included. There was low-certainty evidence that transdermal patches provided statistically and clinically significant pain relief on movement at long-term follow-up for chronic musculoskeletal pain (effect size -2-69 (95% CI: -4.14, -1.24) and at short-term follow-up which was non-clinically significant, (-1.24: 95% CI: -1.78, -0.69). Several types of transdermal anti-inflammatory patches may offer short-term and long-term pain relief for acute and chronic musculoskeletal conditions. However, the clinical significance of this effect for the long-term pain relief was based on low-certainty evidence of transdermal anti-inflammatory patches versus placebo; for short-term pain there was an overall non-clinically significant improvement. Performing a meta-analysis for all outcomes was not possible due to insufficiency in the evidence-base. www.crd.york.ac.uk/prospero identifier is CRD42020185944.