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Abstract Objective This study aimed to investigate and compare the histological response of rabbit dental pulp after direct pulp capping with 3 different materials: mineral trioxide aggregate (MTA), nanoparticles of fluorapatite (Nano-FA), and nanoparticles of hydroxyapatite (Nano-HA) after 4 and 6-week time intervals. Material and methods A total of 72 upper and lower incisor teeth from 18 rabbits were randomly categorized into 3 groups)24 incisors from six rabbits each. MTA Group: teeth were capped with MTA. Nano-FA Group: teeth were capped with fluorapatite nanoparticles. Nano-HA Group: teeth were capped with hydroxyapatite nanoparticles. Blood samples were collected to examine some antioxidant enzymes nitric oxide (NO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione (GSH), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). After that, three rabbits from each group were euthanized after 4 and 6 weeks, respectively. Pulp tissues of all teeth in all groups were histologically observed. Results The obtained results showed that both Nano-HA induced the formation of thick dentin bridges with irregular dentin patterns at 6 weeks, while MTA and Nano-FA induced no dentin bridge with no tubular dentin pattern. Blood examination at the two intervals revealed no significant increase or decrease in the values of NO, SOD, CAT, GPx, GSH, and TNF-α. However, there was a significant increase in p-values of IL-6 in the Nano-FA treated group compared to both MTA and Nano-HA treated groups at the two intervals. Regarding the inflammatory reaction of the dental pulp, the MTA and Nano-HA groups displayed moderate inflammation, followed by Nano-FA, which showed the highest prevalence of nonpathological inflammation. Histological results were consistent with the blood examination. After 4 weeks, the Nano-FA and Nano-HA groups showed pulp fibrosis at the operating site, but the MTA showed only granulation tissues. Plus, dilated blood vessels appeared in the Nano-FA group. After 6 weeks, MTA and Nano-FA groups showed pulp fibrosis at the operating site with the persistence of dilated blood vessels with Nano-FA. The nano-HA group showed dentin bridge formation at the operating site. Conclusion MTA and Nano-HA could be considered favorable materials for direct pulp capping, while Nano-FA produces nonpathological inflammatory cell reactions. Moreover, the Nano-HA was the best in dentin bridge formation. Although nano-FA increased the operating site closure, it was noticed that it significantly increased IL-6 compared to MTA at the two intervals and significantly increased IL-6 compared to Nano-HA at 6 weeks, which may be manifested as some nonpathological inflammations in the Nano-FA group compared to the other groups, but it was deemed acceptable to direct pulp capping procedures.