Background and Objectives: Diagnostic evaluation with the aid of biomarkers has reached newer heights to assess disease activity. Salivary calcium, magnesium, and pH are one of the biochemical parameters which can be helpful in assessing the progression of periodontal disease. Smokers are at topnotch threat for having oral diseases, predominantly periodontal diseases. The aim of this study was to assess the salivary calcium, magnesium, and pH levels in smokers compared with non-smokers with chronic periodontitis. Materials and Methods: The current study was conducted on 210 individuals affected with generalized chronic periodontitis, with the age group between 25 and 55 years. Based on their smoking habit, an equal number of patients were categorized into two groups; namely, group I consisted of non-smokers and group II consisted of smokers. The clinical parameters that were measured included Plaque Index (PI), Gingival Index (GI), Probing Pocket Depth (PPD), and Clinical Attachment Loss (CAL). The biochemical variables that were evaluated in the current study included salivary calcium, magnesium, and pH using an AVL9180 electrolyte analyzer (Roche, Germany). The gathered data were analyzed with an unpaired t test was using SPSS 20.0. Results: A statistically significant higher PPD (p < 0.01), CAL (p < 0.05), and salivary calcium levels (p < 0.001) were observed in the smokers’ compared with their non-smoking counterparts. Among the biochemical parameters, calcium showed a significantly (p < 0.001) higher level in smokers (5.79 ± 1.76) in contrast to non-smokers (3.87 ± 1.03). Additionally, a significant negative correlation (p < 0.05) between calcium and PPD was observed in non-smokers, whereas a non-significant inverse relation (p > 0.05) was seen in smokers. Conclusions: The present study indicates that the salivary calcium level can be a potential biochemical parameter to assess the progression of periodontal disease in smokers and non-smokers. Within the limitations of the current study, the salivary biomarkers appear to have an essential role in the identification and indication of the status of periodontal diseases.