An effective therapeutic approach based on the anti-inflammatory action of hydrogen sulfide (H<sub>2</sub>S) and inhibition of carbonic anhydrases (CAs) IX and XII is proposed here for the management of arthritis. H<sub>2</sub>S 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 H<sub>2</sub>S 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 H<sub>2</sub>S and produce a potent pain-relieving effect in a rat model of arthritis. Compound <b>26</b> completely reverted the pain state 45 min after administration with enhanced antihyperalgesic effect in vivo compared to the single H<sub>2</sub>S donor, CAI fragment, or their co-administration.