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Selenium (Se) is an essential trace element for mammals. Inadequate Se can aggravate the development of inflammatory bowel diseases. Selenium nanoparticles (SeNPs) are characterized by low toxicity and anti-inflammatory properties with functional modifications. Poria cocos polysaccharide (PYN) was purchased from Elicityl. Antibodies included anti-COX-2 and anti-TNF-α were obtained from Cell SignalingTechnology. Cell uptake of PYNSeNPs and SeNPs during the time course was compared and evidenced by images taken by fluorescence microscope. The particle-size distribution of PYN-SeNPs was 35–80 nm, which is smaller compared to 305–900 nm of SeNPs. Acute colitis mice were treated with/without PYNSeNPs and the body weights were measured daily. The effect of PYN-SeNPs on colitis was detected by Hematoxylin-Eosin staining. PYN-SeNPs supplementation may offer therapeutic potential to reduce the symptoms of acute colitis through its anti-inflammatory actions.