This study aims to extract pepsin soluble collagen (PSC) from sturgeon cartilage, hydrolyze to sturgeon cartilage collagen peptides (SCCP), and prepare SCCP nanoliposomes to explore the treatment effects of osteoarthritis (OA) in rats. PSC was extracted using 0.5 M acetic acid and pepsin (10%) and enzymatically hydrolyzed with 4.5% alcalase plus 4.5% flavourzyme to obtain SCCP. Amino acid analysis revealed the presence of glycine, proline, and hydroxyproline in high amounts, while SDS‐PAGE showed that the PSC belonged to type II collagen with molecular weight (MW) of SCCP being <2 kDa and MALDI‐TOF‐MS indicated the MW distribution to range from 302.594 to 683.050 Da with the peptide fragments <500 Da accounting for 89.71%. SCCP nanoliposomes composed of phosphatidylcholine, fatty acid sucrose ester, glycerol, and deionized water were prepared with size at 34.58 nm, polydispersity index at 0.19, zeta potential at ‐54.53 mV, and encapsulation efficiency at 88.14%. Tube feeding of SCCP/SCCP nanoliposomes into OA rats alleviated pain responses by joint damage through reduction in hind limb weight‐bearing difference, knee joint width difference, and levels of serum biomarkers including CTX‐II, TGF‐β1, PIICP, and COMP. Histopathologic images demonstrated the mitigation of joint damage symptoms in the tissue by reducing cartilage joint damage, inhibiting chondrocyte apoptosis, promoting chondrocyte regeneration, and reducing synovitis. Collectively, the high dose of SCCP nanoliposomes was the most effective in alleviating OA possessing a great potential to be developed into a health food or botanic drug for the treatment of joint‐related disease.