Neuroinflammation, characterized by the activation of microglia and astrocytes, is important in the pathogenesis of many neurological disorders, such as Alzheimer’s disease. Nonsteroidal anti-inflammatory drugs (NSAIDs), a group of chemically heterogenous medications, are used widely in the treatment of inflammation. However, the safety of these drugs is a growing concern due to their side effects on the gastrointestinal tract and liver. Royal jelly (RJ) is a potential functional food produced by the hypopharynx and mandibular salivary glands of nurse bees. In this study, we explored the anti-neuroinflammatory effect of 10-hydroxydecanoic acid (10-HDAA), which is the second most abundant but less studied fatty acid in RJ. We showed that 10-HDAA decreased the lipopolysaccharide (LPS)-induced elevation of inducible nitric oxide synthase (iNOS) and nitric oxide (NO) levels in both microglial BV-2 and N9 cell lines. Compared to the LPS group, the 10-HDAA/LPS treated BV-2 cells had a higher level of the phagocytic receptor TREM2. RNAseq transcriptomic results showed a different transcriptional profile between the LPS group and the 10-HDAA/LPS group in BV-2 cells and the 10-HDAA pre-treatment significantly decreased levels of pro-inflammatory mediators, which were further confirmed by qRT-PCR analysis. Moreover, we found that p53 was a target of 10-HDAA. p53 may mediate the anti-inflammation effect of 10-HDAA in two ways: first by directly deactivating the NLRP3 inflammatory pathway, second by indirectly promoting autophagy. Taken together, our results reveal a novel function of tumor suppressor p53 in the inhibition of neuroinflammation and provide a theoretical basis for broadening the application range of 10-HDAA and RJ.