Resin (co)monomers issued from restorative dental materials are able to distribute in the dental pulp or the gingiva, to get to the saliva and to the flowing blood. Many authors have recently shown that methacrylate-based resins, in particular 2-hydroxyethylmethacrylate (HEMA), are responsible of inflammatory and autophagic processes in human dental pulp stem cells (hDPSCs) while ascorbic acid (AS), an antioxidant molecule, can assume a protective role in cell homeostasis. The purpose of the current work was to study if 50 µg/mL AS can affect the inflammatory status induced by 2 mM HEMA in hDPSCs, a tissue-specific cell population. Cell proliferation, cytokine release, morphological arrangement and reactive oxygen species (ROS) formation were determined respectively by MTT, ELISA, morphological analysis and dichlorofluorescein assay. The hDPSCs exposed to HEMA let to an increment of ROS formation and in the expression of high levels of inflammatory mediators such as nuclear factor-κB (NFkB), inflammatory cytokines such as interleukin IL6, IL8, interferon (IFN)ɣ and monocyte chemoattractant protein (MCP)1. Moreover, HEMA induced the up-regulation of pospho-extracellular signal-regulated kinases (pERK)/ERK signaling pathway associated to the nuclear translocation. AS treatment significantly down-regulated the levels of pro-inflammatory mediators. Then, the natural product AS reduced the detrimental result promoted by methacrylates in clinical dentistry, in fact restore cell proliferation, reduce the pro-inflammatory cytokine, downregulate ROS production and of NFkB/pERK/ERK signaling path. In synthesis, AS, could improve the quality of dental care and play a strategic role as innovative endodontic compound easy to use and with reasonable cost.