The strengthening of metallic biomaterials, such as Co-Cr-Mo and titanium alloys, is of crucial importance to the improvement of the durability of orthopedic implants. In the present study, we successfully developed a face-centered cubic (fcc) Co-Cr-Mo alloy with an extremely high yield strength (1400 MPa) and good ductility (12%) by multipass hot-rolling, which is suitable for industrial production, and examined the relevant strengthening mechanisms. Using an X-ray diffraction line-profile analysis, we revealed that a substantial increase in the number of stacking faults (SFs) in the fcc γ-matrix occurred at a greater height reduction (r), while physical modeling demonstrated that the contribution of the accumulated SFs (i.e., the reduction in SF spacing) with an increase in r successfully explains the entire strengthening behavior of the hot-rolled alloy. The present study sheds light on the importance of the SF strengthening mechanism, and will help to guide the design and manufacturing strategy for the high-strength Co-Cr-Mo alloys used in highly durable medical devices.