Background and Objective: Potato, the fourth important commercial crop in the world, is infected by brown rot disease, which is one of the most important bacterial plant disease worldwide. The present investigation aimed to study the influence of Saccharomyces cerevisiae on Ralstonia solanacearum and potato plant resistance to control bacterial wilt disease of potato. Methodology: The ability of S. cerevisiae to inhibit the growth of R. solanacearum in vitro was investigated. In pots experiment, potato slices were soaked in the three different treatments of S. cerevisiae (whole culture, cell-free extract and yeast cells), then cultivated in soil infested with R. solanacearum. The disease rating was recorded. Different systemic induced resistance parameters were estimated. The increase of the weight of tubers and the decrease of the percentage of infected tubers were calculated. The total count of bacteria, fungi and yeast of soil microflora of potato plant rhizosphere were enumerated. The one-way randomized blocks design was applied in pots experiment. Data were analyzed with the statistical analysis software packages CoStat. Results: The S. cerevisiae did not inhibit R. solanacearum in vitro. It was found to produce indole acetic acid, gibberellic acid and cytokinin in the amounts of 81.57, 464.56 and 4.37 µg mLG1, respectively. In pots experiment, the three studied treatments of S. cerevisiae significantly increased (p<0.05) the plant height and decreased the disease rating. The total phenols, flavonoids, polyphenol oxidase, peroxidase, ABTS, DPPH, reducing power and gibberellic acid were significantly increased (p<0.05) as a response to the three studied treatments after 40 and 70 days of planting. Moreover, the antioxidant capacity, starch content were significantly increased (p<0.05). While sugar contents of potato tubers were significantly decreased (p<0.05). The rhizosphere microflora showed various responses. Conclusion: It was concluded that the cell-free extract was the best treatment that could be recommended as a safe and economic bio-agent for the management of bacterial wilt disease of potato. © 2017 Zeiad Moussa et al . This is an open access article distributed under the terms of the creative commons attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original author and source are credited.