Objective: This study aimed to evaluate the effect of multivitamin supplementation on fatigue reduction in general practice patients. Methodology: A randomized controlled trial was conducted with 100 participants aged 16–85 years, who were randomly assigned to either an intervention group receiving multivitamin supplements or a control group receiving a placebo. Data were collected through self-reported fatigue, mood, and stress scales at baseline and after 4 weeks of supplementation. Statistical analysis was performed using paired t-tests and multivariate analysis to assess within-group and between-group differences. Results: The findings of this study revealed that multivitamin supplementation led to a significant reduction in fatigue levels among participants in the intervention group compared to the control group. After a 4-week period, the intervention group experienced a notable decrease in fatigue, with an average reduction of 30% (p < 0.05), whereas the control group showed only a marginal change. In addition to fatigue reduction, the intervention group also exhibited substantial improvements in mood and stress levels. Mood scores increased by an average of 1.7 points (p < 0.01), and stress levels decreased by 1.7 points (p < 0.05). The most pronounced benefits were observed in participants with deficiencies in vitamin D, iron, and magnesium, suggesting that individuals with specific micronutrient deficiencies may experience greater relief from fatigue. These results strongly indicate that multivitamin supplementation is an effective intervention for alleviating fatigue and enhancing psychological well-being, particularly in individuals with underlying nutritional deficiencies. Conclusion: The study demonstrated that multivitamin supplementation effectively reduced fatigue and improved psychological well-being in general practice patients, particularly those with micronutrient deficiencies. The intervention group showed significant improvements in fatigue levels, mood, and stress compared to the control group, highlighting the potential of multivitamins as a practical and accessible solution for managing fatigue. These findings support the use of multivitamin supplementation as a cost-effective strategy to enhance overall health and quality of life, particularly in individuals with nutrient deficiencies. Further studies are needed to investigate the long-term effects and mechanisms underlying these benefits.