Herein we report the design as well as the synthesis of a new series of dual hybrid compounds consisting of the therapeutically used nonsteroidal-anti-inflammatory drugs (NSAIDs; i.e., indometacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) and the carbonic anhydrase inhibitor (CAIs) fragments of the sulfonamide type. Such compounds are proposed as new tools for the management of ache symptoms associated with rheumatoid arthritis (RA) and related inflammation diseases. The majority of the hybrids reported were effective in inhibiting the ubiquitous human (h) CA I and II as well as the RA overexpressed hCAs IX and XII isoforms, with KI values comprised of the low-medium nanomolar ranges. The antihyperalgesic activity of selected compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model, and among them the hybrids 6B and 8B showed potent antinociceptive effects lasting up to 60 min after administration.