Chondrocyte apoptosis is closely related to the development and progression of osteoarthritis. Ginsenoside Rg1 protects cells by antagonizing apoptosis. This study aimed to investigate the protective effect of Rg1 on interleukin 1β (IL-1β)-induced chondrocyte apoptosis and the underlying molecular mechanisms. Chondrocytes were harvested from the joints of 1-week-old Sprague-Dawley rats. After treated with 10 μg/mL Rg1 for 2 h, the chondrocytes were cultured with 10 ng/mL IL-1β to induce cytotoxicity. Cell viability was assessed with MTT assays. Annexin V/propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick-end labeling were used to detect chondrocyte apoptosis. The contents of total Akt, phosphorylated Akt (p-Akt), Bcl-2, Bax, and cytochrome C (Cyt c) were determined by Western blotting assay. A quantitative colorimetric assay was used to determine caspase-3 activity. Our present findings have shown that pre-treatment of chondrocytes with Rg1 reduces IL-1β induced cytotoxicity/apoptosis. Rg1 pretreatment also decreases the activity of IL-1β that reduces expression of Bcl-2 and level of p-Akt, and increases Bax activity, Cyt c release, and caspase-3 activation. It also reverses the activity of IL-1β that reduces the expression of tissue inhibitor of metalloproteinase-1 expression and increased the synthesis of matrix metalloproteinase-13, with the net effect of inhibiting extracellular matrix degradation. These results indicate that Rg1 may protect chondrocytes from IL-1β-induced apoptosis via the phosphatidylinositol 3-kinase/protein kinase B signaling pathway, through preventing caspase-3 release.