Neuroinflammation plays a central role in multiple neurodegenerative diseases and neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), cerebral ischemic injury etc. In this connection, microglia, the key players in the central nervous system, mediate the inflammatory response process. In brain injuries, activated microglia can clear the cellular debris and invading pathogens and release neurotrophic factors; however, prolonged microglia activation may cause neuronal death through excessive release of inflammatory mediators. Therefore, it is of paramount importance to understand the underlying molecular mechanisms of microglia activation to design an effective therapeutic strategy to alleviate neuronal injury. Recent studies have shown that some natural compounds and herbal extracts possess anti-inflammatory properties that may suppress microglial activation and ameliorate neuroinflammation and hence are neuroprotective. In this review, we will update some of the common signaling pathways that regulate microglia activation. Among the various signaling pathways, the Notch-1, mitogen-activated protein kinases (MAPKs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) have been reported to exacerbate microglia mediated neuroinflammation that is implicated in different neuropathological diseases. The search for natural compounds or agents, specifically those derived from natural herbal extracts such as Gastrodin, scutellarin, RG1 etc. has been the focus of many of our recent studies because they have been found to regulate microglia activation. The pharmacological effects of these agents and their potential mechanisms for regulating microglia activation are systematically reviewed here for a fuller understanding of their biochemical action and therapeutic potential for treatment of microglia mediated neuropathological diseases.