This study aimed to assess the effect of apical periodontitis and its treatment on the profile of salivary inflammatory markers and to investigate its correlation with serum inflammatory markers. Saliva samples were collected from 115 recruited participants. Patients were reviewed after 1 and 2 years following treatment. Saliva samples were analysed using Multiplex microbead immunoassay for identifying the inflammatory biomarkers’ profile. Biomarker levels were compared against healthy controls at baseline. Longitudinal comparison of those markers was further analysed for the review appointments and correlated with the size of the periapical radiolucency, treatment outcome and serum inflammatory biomarker levels. The salivary cytokines, matrix metalloproteinases (MMPs) and vascular adhesion molecules were higher at the review appointments. Pre-operative salivary levels of high-sensitivity C-reactive protein (hs-CRP) were significantly higher in the treatment group than in the control group (p < 0.001). At 1 year, hs-CRP was decreased than baseline. While, in 2 years, fibroblast growth factor (FGF)-23 was significantly lower compared to baseline levels (p = 0.005). Furthermore, the post-operative size of radiolucency was significantly correlated with the levels of several markers. When correlating the salivary levels of biomarkers with the serum levels, a significant correlation was seen in FGF-23 (p = 0.04) at baseline; in intercellular adhesion molecule (ICAM)-1 (p = 0.02) at 1 year post-treatment; and in TNF-α, ICAM-1 and E-Selectin at 2 years post-treatment (p = 0.046; p = 0.033; p = 0.019, respectively). Therefore, his study suggests that higher salivary cytokines, MMPs and vascular adhesion molecules at the post-treatment reviews are related to periapical bone healing and remodelling, whereas salivary FGF-23 and hs-CRP could be prognostic biomarkers. Correlation of some salivary with serum biomarkers suggests that saliva sampling could be a feasible non-invasive option for the measurement of inflammatory marker levels; however, further longitudinal studies are required.