This study aimed to use intact mineral trioxide aggregate (MTA) as a root canal sealer by hydrophilizing the gutta-percha (GP) surface. The GP specimens were treated with atmospheric air plasma, cetylpyridinium chloride (CPC), or a combination of both. The wettability and surface chemical properties were evaluated using contact angle measurements and X-ray photoelectron spectroscopy (XPS). The physicochemical properties of MTA mixed with water or 100 mM of CPC solution were evaluated using setting time, flowability, compressive strength, and X-ray diffraction (XRD) analyses. Sealing ability was assessed by evaluating the dye penetration in obturated single-rooted teeth. Combined plasma and CPC treatment significantly decreased the contact angle of GP compared to that of the untreated group (p < 0.05) and showed the least hydrophobic recovery after 8 weeks. The XPS analysis confirmed the adsorption of CPC onto the GP surface. The XRD and compressive strength results indicated that the CPC did not interfere with the setting reaction of intact MTA, although the setting time was prolonged (p < 0.05). Dye penetration was significantly reduced in the plasma- and CPC-treated GP groups compared to the untreated GP group (p < 0.05), with a sealing ability comparable to that of the zinc oxide-based sealer.