Tissue swelling represents an early sign of osteoarthritis, reflecting osmolarity changes from iso- to hypo-osmotic in the diseased joints. Increased tissue hydration may drive cell swelling. The opposing cartilages in a joint may swell differently, thereby predisposing the more swollen cartilage and cells to mechanical injuries. However, our understanding of the tissue–cell interdependence in osmotically loaded joints is limited as tissue and cell swellings have been studied separately. Here, we measured tissue and cell responses of opposing patellar (PAT) and femoral groove (FG) cartilages in lapine knees exposed to an extreme hypo-osmotic challenge. We found that the tissue matrix and most cells swelled during the hypo-osmotic challenge, but to a different extent (tissue:​ <3%, cells:​ 11%–15%). Swelling-induced tissue strains were anisotropic, showing 2%–4% stretch and 1%–2% compression along the first and third principal directions, respectively. These strains were amplified by 5–8 times in the cells. Interestingly, the first principal strains of tissue and cells occurred in different directions (60–61° for tissue vs. 8–13° for cells), suggesting different mechanisms causing volume expansion in the tissue and the cells. Instead of the continuous swelling observed in the tissue matrix, >88% of cells underwent regulatory volume decrease to return to their pre-osmotic challenge volumes. Cell shapes changed in the early phase of swelling but stayed constant thereafter. Kinematic changes to tissue and cells were larger for PAT cartilage than for FG cartilage. We conclude that the swelling-induced deformation of tissue and cells is anisotropic. Cells actively restored volume independent of the surrounding tissues and seemed to prioritize volume restoration over shape restoration. Our findings shed light on tissue–cell interdependence in changing osmotic environments that is crucial for cell mechano-transduction in swollen/diseased tissues.