Plant-derived natural products have long been a vital source for developing therapeutic drugs. Wedelolactone (WDL), a coumestan isolated from Eclipta prostrata, Wedelia calendulacea, Wedelia chinensis, and Sphagneticola trilobata, demonstrates a broad spectrum of therapeutic potential, including anticancer, anti-inflammatory, anti-obesity, anti-myotoxic, antimicrobial, anti-diabetic, and tissue-protective activities. This review synthesizes information on the isolation, total synthesis, pharmacological activity, underlying mechanisms, and pharmacokinetic properties of WDL. Additionally, it offers insights into potential clinical applications and future drug discovery avenues utilizing WDL or its derivatives, either independently or in combination with other pharmaceuticals.