In recent years, the Zika Virus (ZIKV) has caused pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZS). Although all strains associated with worldwide outbreaks derive from the Asian lineage, the reasons for their enhanced spread and severity are not fully understood. In this study, we conducted a comparative analysis of miRNAs (miRNA-155/146a/124) and their cellular targets (SOCS1/3, SHP1, TRAF6, IRAK1), as well as pro- and anti-inflammatory and anti-viral cytokines (IL-6, TNF-α, IFN-γ, IL-10, and IFN-β) and peroxisome proliferator-activated receptor γ (PPAR-γ) expression in BV2 microglia cells infected with ZIKV strains derived from African and Asian lineages (ZIKV_MR766 and ZIKV_PE243). BV2 cells were susceptible to both ZIKV strains, and showed discrete levels of viral replication, with delayed release of viral particles without inducing significant cytopathogenic effects. However, the ZIKV_MR766 strain showed higher infectivity and replicative capacity, inducing a higher expression of microglial activation markers than the ZIKV_PE243 strain. Moreover, infection with the ZIKV_MR766 strain promoted both a higher inflammatory response and a lower expression of anti-viral factors compared to the ZIKV_PE243 strain. Remarkably, the ZIKK_PE243 strain induced significantly higher levels of the anti-inflammatory nuclear receptor—PPAR-γ. These findings improve our understanding of ZIKV-mediated modulation of inflammatory and anti-viral innate immune responses and open a new avenue to explore underlining mechanisms involved in the pathogenesis of ZIKV-associated diseases.