Fast degradation rate and inhomogeneous corrosion are obstacles for magnesium alloy bio-corrosion properties. In this paper, a quaternary Mg-Zn-Ca-Mn alloy was designed by an orthogonal method and prepared by vacuum induction melting to investigate its bio-corrosion. Microstructure, corrosion morphology, and bio-corrosion properties of as-cast alloys 1 to 5 with good corrosion resistance were characterized by scanning electron microscopy, energy dispersive X-ray spectroscopy, and X-ray diffraction with immersion and electrochemical tests in simulated body fluid (SBF), respectively. Both the orthogonal method and in vitro degradation experiments demonstrated that alloy 3 exhibited the lowest degradation rate among the tested quaternary Mg-Zn-Ca-Mn alloys. Then, as-cast alloy 3 was treated by solid-solution and solid-solution aging. In vitro experimental results indicated that as-cast alloy 3 showed better corrosion resistance than heat-treated specimens and the average corrosion rate was approximately 0.15 mm/y. Heat-treated alloy 3 exhibited more uniform corrosion than as-cast alloy specimens. These results suggest that alloy 3 has the potential to become a biodegradable candidate material.