An effective therapeutic approach based on the anti-inflammatory action of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs) IX and XII is proposed here for the management of arthritis. H2S is a human gasotransmitter that modulates inflammatory response at low concentrations. Inhibition of CAs IX and XII can repristinate normal pH in the acidic inflamed synovial fluid, alleviating arthritis symptoms. We report here the design of H2S donor─CA inhibitor (CAI) hybrid derivatives. The latter were tested in vitro as inhibitors of human CAs I, II, IV, IX, and XII, showing a markedly increased inhibition potency/isoform selectivity compared to the CAI synthetic precursors. The best compounds demonstrated the ability to consistently release H2S and produce a potent pain-relieving effect in a rat model of arthritis. Compound 26 completely reverted the pain state 45 min after administration with enhanced antihyperalgesic effect in vivo compared to the single H2S donor, CAI fragment, or their co-administration.