The knowledge-based companies are formed by a group of educated entrepreneurs to use and commercialize innovative ideas. Technical and advanced knowledge would open the way for the entry and competition of national productions into the global markets and have a significant effect on domestic self-sufficiency and foreign trade, in this regard the knowledge-based companies in the science and technology parks are being supported by specialized incubators for growth, development and maturity. The main purpose of this study was to identify and analyze the challenges of the companies located in the Science and Technology Park from the point of view of the park managers and companies. In this qualitative research, the case study method was used. Purposeful sampling and snowball techniques were used to select the key informants of in-depth interviews. The data was gathered through semi-structured interviews with a special protocol. Required data was gathered through interviews with 17 managers of Science and Technology Park and the CEOs of knowledge-based companies located in Fars Science and Technology Park. The data analysis was accomplished by MAXQDA₂₀₂₀ software. According to the findings, the companies are facing two types of challenges. The first category is the challenges related to the processes and internal executive affairs of the park during its acceptance and establishment in the park. The second one is the external challenges, which include administrative bureaucracy, exemptions, and the instability of the business environment. These challenges cause a lot of problems for newly founded and young companies because they do not have access to enough resources to be resilient in difficult situations. Based on the results, the acceptance process of companies needs to be changed. The admission time should be shortened so that the entrepreneurs do not give up on admission. It is required to pay special attention to companies and their type of activities in terms of providing better and more related services and facilities. The dedicated space should also be in accordance with the basic needs of these companies. It is more effective that the method of paying the loans should be in accordance with a purposeful schedule and appropriate to the companies` activities. Also, more practical training is provided to companies through people who have great experience in the entrepreneurship area. On the other hand, it needs to have a stronger network system for companies so they can collaborate and learn from each other, attract more customers, and succeed in the market