Carboxymethyl cellulose (CMC)/pPoly-N-isopropylacrylamide (PNIPAM) hydrogels were prepared using nanoclay as physical cross-linker by UV irradiation. PNIPAM/CMC hydrogels exhibit 3D network structures with high porosity. PNIPAM/CMC hydrogels exhibit not only high water absorption capacity, but also temperature, pH and salt mutiple-responsive swelling performance. Besides, they exhibit reversible swelling behavior in alternate de-ionized water and NaCl solution. Moreover, the fabricated PNIPAM/CMC hydrogels display great compression mechanical property. Then, tetracycline hydrochloride (TCH) was loaded into the PNIPAM/CMC hydrogels to endow their antibacterial ability. TCH loaded PNIPAM/CMC hydrogels exhibit excellent antibacterial activity against E. coli and B. subtilis and good biocompatibility. Thus, the PNIPAM/CMC composite hydrogels with triple stimuli-responsive swelling performances reported herein have great potentials in many biomedical applications.