Radiation therapy for head and neck cancer frequently causes salivary gland dysfunction. Pilocarpine is a clinically approved and effective drug that induces saliva secretion, thereby keeping the oral mucosa moist and reducing discomfort in patients, but the effect is transient. We expected that this drug also has beneficial long-term effects that maintain the integrity of salivary glands by reducing, for instance, apoptosis. Here, we examined the effects of long-term pilocarpine administration in irradiated mice. The results indicated that long-term pilocarpine administration significantly improved salivary flow in irradiated mice, suggesting the potential beneficial effects of long-term administration. To elucidate the underlying mechanism, we analyzed the histology, apoptosis, and proliferation of acinar cells, and the expression of functional membrane proteins such as transmembrane member 16A, aquaporin-5, and Na-K-Cl cotransporter. Long-term pilocarpine treatment seemed to decrease irradiation-induced apoptosis, although the change was not statistically significant. The present results indicated that long-term administration of pilocarpine has beneficial effects on salivary flow in irradiated mice, and suggested that long-term administration possibly decreases apoptosis in irradiated salivary glands.