The market demand for biopharmaceuticals, the leading drugs in the pharmaceutical industry, has promoted the development of various protein expression hosts and bioprocessing technologies. While advances in the field of recombinant protein production have changed the previous situation, resulting in increased production and reduced costs, industrialized production helped in the treatment of a variety of diseases. Since mammalian cells have the unique advantages of being able to direct the correct folding of proteins and provide post-translational processing such as complex glycosylation the recombinant protein drugs produced by them currently account for approximately 80% of the approved marketed protein drugs, while Chinese hamster ovary (CHO) cells are currently the preferred host cells for the production of recombinant protein drugs. Obtaining recombinant protein drugs involves the synthesis, processing, transport, and secretion of proteins, and the secretion of proteins greatly limits the manufacturing of recombinant protein drugs. Here, we review the current research status of CHO cells as an important engineering tool for recombinant protein drug expression systems, focus on the recombinant protein secretion process of CHO cells and its influencing factors, and discuss the optimization strategy for recombinant protein secretion and expression in CHO cells.