Buruli Ulcer (BU) is a serious neglected, tropical infectious disease of the skin and the subcutaneous tissue caused by M. ulcerans. From surgery to successful introduction of the right cocktail of antibiotic therapy, different alternative and/or complementary treatments have been implemented. Looking for those that overcome disadvantages/limitations often present in current therapies such as costs, treatment length, resistance, toxic side/adverse effects, frequent relapses, this book wants to highlight the importance of oxygen-ozone (O2-O3) therapy as a strategic new intervention treatment for BU. O3 at mild concentrations could represent a convenient, inexpensive therapy, working in absence of side effects that permit to modulate the host immune, inflammatory, oxidant systems besides to destroy the bacterium. We describe wide literature demonstrating the potentiality of this molecule: from anti-microbial, to immune/anti-inflammation, pro-autophagy activities, enhancement in therelease of growth factors from platelets, improvement in blood circulation and O2 delivery to damaged tissues, and up-regulation of cellular antioxidant enzyme activity.