Background and Objectives: The purpose of this study was to assess pyrexia and sickness behavior such as anxiety, depression, lethargy, and weight loss in subjects with chronic periodontitis, and evaluate inflammatory mediators such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the patients with fever. Methods: This was a cross-sectional study that consisted of 150 chronic periodontitis and 150 healthy subjects. Sublingual and subgingival temperatures were assessed using a digital temperature probe. Associated sickness behavior was assessed for all the subjects. Pathological tests, i.e., ESR and CRP were done for subjects with fever. Results: Evaluating the presence of fever with the severity of periodontal disease, 66.7% of the subjects with fever were in the group diagnosed with severe periodontitis, 20.4% had with moderate periodontitis, and 5.3% were in the healthy group. Subjects diagnosed with periodontitis comprised 66.2% of the subjects with higher (i.e., > 36.3°C) subgingival temperatures and healthy subjects made up the remaining 33.8% (p < 0.001). A correlation between the sublingual and subgingival temperature with the Pearson ρ correlation coefficient of 0.227 (p < 0.001) was observed. A statistically significant mean value of 37.05 ± 11.24 of ESR and 1.59 ± 1.11 mg/L of CRP was reported amongst the subjects with fever (p < 0.001). The association of sickness behavior with the severity of periodontitis was found to be significant: depression 40.006, anxiety 50.857, reported weight loss 76.463, and lethargy 141.581 (p < 0.001). Discussion and Conclusion: The study demonstrated that there is a significant increase in the sublingual temperature amongst patients with severe chronic periodontitis. The subgingival temperature has a positive correlation with the sublingual temperature. There was a linear trend of an association of sickness behavior with the severity of chronic periodontitis. A significant increase in the circulating inflammatory mediators, CRP and ESR, were noticed in subjects with elevated body temperature.