<p>Carbenoxolone (CBX) is a glycyrrhetinic acid derivative with potential anti-inflammatory and pain-relieving properties&#xa0;shown by clinical and preclinical studies. In animal studies, CBX reduced pain hypersensitivity by inhibiting gap junction communication, reducing neuroinflammation, and increasing gamma-aminobutyric acid (GABA)-ergic signaling.</p><p>We reviewed analgesic and anti-inflammatory effects of CBX reported by preclinical (<i>n</i> = 15) and clinical (<i>n</i> = 8) studies following a systematic search in PubMed and Scopus, and discuss its safety profile and kinetic properties. The preclinical studies on rodents employed behavioral pain assessments such as paw withdrawal, head withdrawal, tail flick, licking behavior, and formalin-induced responses, and clinical studies used scoring to record pain severity. Preclinical data indicated the effectiveness of CBX in reducing mechanical, thermal, and chemical hypersensitivity. In clinical studies, topical CBX accelerated lesion healing in herpes-associated pain and oral CBX promoted recovery in peptic ulcers; nevertheless, its role in symptom relief was inconsistent and often secondary to tissue healing. CBX also demonstrated broad anti-inflammatory activities across various models, primarily through the inhibition of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and IL-6, suppression of NF-κB and NLRP3 inflammasome signaling, and reduction of oxidative stress markers inducible nitric oxide synthase (iNOS), reactive oxygen species (ROS), and nitric oxide (NO). Noteworthy, side effects of CBX include sodium retention, weight gain, electrolyte imbalances, hypokalemia, mild edema, elevated blood pressure, headache, and heartburn. Given the strong preclinical evidence&#xa0;but&#xa0;limited clinical validation, further research is needed to clarify CBX analgesic/anti-inflammatory mechanisms/efficacy and fully elucidate its safety profile.</p> Graphical abstract <p></p>