Sodium chloride (NaCl) serves as a necessary stabilizer for some proteins, yet it presents an unfriendly eutectic melting temperature and can easily lead to collapse for lyophilized products. Mannitol, serving as bulking agent with property of high eutectic melting point, can provide good mechanical support for lyophilized cake to avoid collapse, therefore it is applied for lyophilized formulations containing NaCl. However, the combination of NaCl and mannitol in formulations often results in structural collapse in lyophilization process due to unproper ratio or lyophilization recipe. In this study, the strategy to improve cake appearance with formulations containing NaCl and mannitol has been explored. The suitable lyophilization formulation compositions and lyophilization process parameters have been proposed with acceptable protein stability. Furthermore, the possibility of mutual inhibition by NaCl and mannitol crystallization is revealed by result of XRD, in which various mannitol crystal forms are observed. It is speculated that protein concentration and lyophilization process parameters are main factors to affect mannitol crystal forms. Our studies not only provide insights into the crystallization behaviors in NaCl-mannitol-protein-based formulations, but also find the strategies to improve the appearance of their lyophilized biopharmaceuticals, facilitating their widespread applications in pharmaceutical development.