Plant beneficial microorganisms improve the health and growth of the associated plants. Application of beneficial microbes triggers an enhanced resistance state, also termed as induced systemic resistance (ISR), in the host, against a broad range of pathogens. Upon the activation of ISR, plants employ long-distance systemic signaling to provide protection for distal tissue, inducing rapid and strong immune responses against pathogens invasions. The transmission of ISR signaling was commonly regarded to be a jasmonic acid- and ethylene-dependent, but salicylic acid-independent, transmission. However, in the last decade, the involvement of both salicylic acid and jasmonic acid/ethylene signaling pathways and the regulatory roles of small RNA in ISR has been updated. In this review, the plant early recognition, responsive reactions, and the related signaling transduction during the process of the plant–beneficial microbe interaction was discussed, with reflection on the crucial regulatory role of small RNAs in the beneficial microbe-mediated ISR.