MicroRNA functions as an important part of the activity and development of immune cells. miR-499 has been demonstrated to play a significant role in the activity and development of immune cells. The precise mechanism by which miR-499 regulates the inflammatory response, however, remains unclear. This study was aimed to examine the role of microRNA miR-499 in the regulation of the inflammatory response in macrophages. RAW 264.7 macrophages were used as a cell model. The levels of miR-499 were measured in Porphyromonas gingivalis LPS-stimulated macrophages using qRT-PCR, and the levels of inflammatory cytokines (IL-6, IL-1β, and TNF-α) were determined using both qRT-PCR and ELISA. StarBase was used to predict the binding sites between NRIP1 and miR-499, and the mRNA expression of NRIP1 was measured using qRT-PCR. The regulation of inflammatory factors controlled by miR-499 was also evaluated by using miR-499 inhibitor and sh-NRIP1. The activation of the JAK/STAT pathway was determined using western blotting to measure the levels of phosphorylated JAK2 and STAT1. Porphyromonas gingivalis LPS caused a high expression of miR-499, which promoted the inflammatory response in macrophages. miR-499 targeted the NRIP1 3' UTR and regulated the mRNA expression of inflammatory cytokines, including IL-6, IL-1β, and TNF-α. The positive correlation between miR-499 and the expression of inflammatory factors and the negative correlation between NRIP1 and miR-499 suggests that the regulation of inflammatory factors controlled by miR-499 was associated with NRIP1. The phosphorylated proteins of the JAK/STAT pathway (p-JAK2 and p-STAT1) were activated by miR-499 through its regulation of NRIP1. These findings suggest that miR-499 regulates the P. gingivalis LPS-induced inflammatory response in macrophages and activates the JAK/STAT pathway through the regulation of NRIP1.