Objective To investigate the effect of naringenin (NAR) on microglial activation in oxygen-induced retinopathy (OIR) based on the microRNA (miR)-223 / nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) axis. Methods Seven-day-old (P7) C57BL/ 6J mice ( n= 150) were divided into normoxia, OIR, NAR, NAR + negative RNA control and NAR + miR-223 antagomir groups with 30 mice per group. Except for mice in the normoxic group, the young mice and their mothers were moved to a closed oxygen box with an oxygen volume fraction of (75 ± 2)% for 5 consecutive days from P7~ P12 and subsequently returned to a normoxic environment; the normoxic group was raised in a normoxic environment. The 12-day-old mice in the NAR groups were injected intraperitoneally with 100 mg / (kg ·d) NAR. The mice in the NAR + negative RNA control group were also injected with 2. 5 mg / kg miR-223 negative control RNA via the tail vein, and mice in the NAR + miR-223 antagomir group were injected with 2. 5 mg / kg miR-223 antagomir via the tail vein. Mice in the normoxic and OIR groups were intraperitoneally injected with an equal volume of carboxymethyl cellulose and tail vein-injected with an equal volume of normal saline each day. For evaluation of retinas in the young mice, real time quantitative PCR (RT-qPCR) was used to detect the level of miR-223; fundus fluorescein angiography was performed; hematoxylin eosin staining was used to observe morphology; immunofluorescence was used to detect the expression of the microglia marker calcium binding protein-1 (Iba-1); and Western blot were used to detect the expression NLRP3, cysteinyl aspartate-specific proteinase-1 ( Caspase-1), interleukin ( IL)-1β and IL-18. Results In the OIR group, blood vessels were ruptured, fluorescence leaked in the retina, the retinas were white, blood vessels were contracted, the retinas were thickened, cell arrangement was loose, and some cells were missing and angiogenesis occurred. In the NAR and NAR + negative RNA control groups, vascular rupture and retinal whitening were alleviated, but retinal cells were still loosely arranged. In the NAR + miR-223 antagomir group, vessels were ruptured, fluorescence leaked in the retina, retinal whitening was obvious, and retinal cells were severely loosened and missing. Compared with that in the normoxic group, miR-223 levels in retinas of the OIR mice decreased (P<0. 05), and the retinal levels of Iba-1, NLRP3, Caspase-1, IL-1β, IL-18 increased (P<0. 05). Compared with that in the OIR group, miR-223 levels in the retinas from the NAR and NAR + negative RNA control groups increased (P<0. 05), and retinal levels of Iba-1, NLRP3, Caspase-1, IL-1β and IL-18 decreased (P<0. 05). Compared with that in the NAR and NAR + negative control groups, retinal levels of miR-223 in the NAR + miR-223 antagomir group decreased (P<0. 05), and the levels of Iba-1, NLRP3, Caspase-1, IL-1β and IL-18 increased (P<0. 05). Conclusions NAR increased the expression of miR-223 and inhibited components of the NLRP3 inflammasome, thus alleviating the over-activation of microglia and reducing OIR.