Background and Aim: Alzheimer's disease (AD) is the most common cause of dementia, and neuroinflammation and tumor necrosis factor-alpha (TNF-α) play a role in its pathogenesis. Considering the side effects of existing medications, non-pharmacological interventions have gained attention. This study aimed to investigate the independent and combined effects of aerobic exercise and ethanolic extract of Salvia officinalis on locomotor-exploratory performance and TNF-α levels in an animal model of AD. Materials and Methods: In this experimental study, 48 male Wistar rats (weight: 270–300 g; age: 8–10 months) were divided into five groups: diseased control, sham, Salvia officinalis extract (50 mg/kg, intraperitoneally, 7 days per week), aerobic exercise (8 weeks, 3 sessions per week), and aerobic exercise + Salvia officinalis extract. Eight healthy rats were also considered as the healthy control group. AD was induced by a single intraperitoneal injection of trimethyltin (10 mg/kg). Locomotor-exploratory performance was assessed using the open field test, and TNF-α was evaluated by real-time PCR. Data were analyzed using one-way ANOVA and Tukey's post hoc test. Findings: AD induction caused a significant decrease in the distance traveled (p = 0.001), time spent in the center of the field (p = 0.001), and number of rearings (p = 0.001), and a significant increase in the number of defecations (p = 0.001) and TNF-α levels compared to the healthy control (p = 0.001). Both individual interventions improved behavioral indices and reduced TNF-α (p = 0.001). The combined intervention was more effective than either individual intervention (p = 0.001), and the greatest reduction in TNF-α was observed in this group. Conclusion: Aerobic exercise and Salvia officinalis extract improve locomotor-exploratory performance in an animal model of AD by reducing TNF-α and modulating inflammatory responses. The combination of these interventions showed a synergistic effect and can be considered as a non-pharmacological approach to help slow the progression of the disease.