An underlying pro-inflammatory status is related to recurrence and persistence of inflammatory susceptibility in obesity and periodontitis, two of the most prevalent chronic inflammatory diseases. Elevated levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), part of the inflammatory network linking these two conditions, persist even after periodontal treatment, with high salivary cytokine levels being linked to overweight and obesity risk. This trial assessed the effect of a novel composition comprising olive oil, trimethylglycine and xylitol, delivered topically to the oral mucosa, on salivary cytokines in periodontally healthy normal and overweight/pre-obese individuals. In a randomized placebo-controlled double-blind clinical trial, adult patients were randomly assigned to use a test toothpaste (intervention group, IG) or a placebo toothpaste (control group, CG) three times a day for 1 month. Primary outcomes were levels of salivary cytokines IL-1β, TNF-α and interleukin-4 (IL-4). Significant differences between IG and CG were observed for IL-1β (p = 0.003; Z = 2.901; r = 0.62) and TNF-α (p = 0.001; Z = 3.23; r = 0.69), but not for IL-4 (p = 0.203; Z = 1.321; r = 0.28). A significant reduction in IL-1β (p = 0.008) and a near significant reduction in TNF-α (p = 0.059) was found in the IG at the end of the trial. Additionally, the effect of body mass index on cytokine levels response was analyzed. A significantly different behavior was shown between IG and CG in the overweight/pre-obesity subgroup for IL-1β (p = 0.014; Z = 2.430; r = 0.63) and TNF-α (p = 0.029; Z = 2.199; r = 0.57). Moreover, a significant decrease in IL-1β in the IG (p = 0.028) was observed. The rapid reduction in IL-1β and TNF-α after 1 month of use of the intervention composition suggests a safe and effective novel strategy for reducing pro-inflammatory cytokines that may offer an opportunity to diminish the inflammatory status in patients with overweight/pre-obesity.