A number of [(3-chlorophenyl)piperazinylpropyl]pyridazinones and the corresponding isoxazolopyridazinones, showing the arylpiperazinyl substructure present in very potent antinociceptive agents reported in the literature, were synthesized and tested for their analgesic activity. The investigated compounds showed antinociceptive properties in the mouse hot-plate test (thermal nociceptive stimulus) after systemic administration with an efficacy similar to that exerted by morphine. The increase of the pain threshold induced by the compounds labeled 5a, 7, 8, and 11 was prevented by reserpine, suggesting the involvement of the noradrenergic and/or serotoninergic system in their mechanism of action. Among them, 7 and 11 showed the highest analgesic potency and efficacy together with a good ratio (133 and 200, respectively) of the minimal nontoxic dose (MNTD) to the minimal analgesic dose (MAD). Furthermore, they were also active after icv administration and in the presence of a chemical, painful stimulus (abdominal constriction test).