Microglia plays a critical role in central nervous system (CNS) homeostasis. Before a traumatic or metabolic injury, is characterized by morphological and biochemical alterations. These mechanisms are given in response to inflammatory stimuli and lead to the secretion of inflammatory mediators (cytokines) that can directly affect cell viability and functioning. In this context, the modulation of microglial activation can be considered as a potential therapeutic strategy to protect against brain injuries or neurodegenerative processes. Recent evidence shows that the use of estrogenic compounds (neuroactive steroids) can provide a protective effect that counteracts brain damage by regulating glial activation processes. We studied the effect of tibolone in a microglial model simulating a metabolic inflammatory environment with palmitic acid. To provide evidence on the protective effect of tibolone, its action on an improvement in cell viability, oxidative stress and mitochondrial function was determined. The protective mechanism of tibolone was shown to be preferentially associated with estrogen receptor beta, which was evidenced by blocking and pharmacological activation of estrogen receptors. Additionally, it was demonstrated that tibolone decreases oxidative stress by modulating the expression of enzymes and proteins responsible for antioxidant regulation, and likewise tibolone increases the expression of neuroglobin, a protein that has been widely reported in neurons by their Protective effects. At the same time, tibolone exerts a protective effect by regulating the expression of pro-inflammatory and antiinflammatory cytokines, as well as the translocation of the p65 subunit of the transcription factor NF-kB regulating the inflammatory process.