Chronic kidney disease (CKD) is a global health problem. CKD causes patients to be hospitalized for a longer time to treat the disease. The impact of the hospitalization brings major changes and affects the quality of life (QoL) of the patients. In this study, we aimed to evaluate the impact of hospitalization on the QoL of patients with CKD. A cross-sectional study was conducted at the inpatient departments (IPDs) and outpatient departments (OPDs) of selected hospitals, in the eastern region of Saudi Arabia. The kidney disease quality of life (KDQOL) scale was used for the data collection and the findings were analyzed. The hospitalized patients had a poorer QoL than the OPD patients. The physical component summary (PCS) and mental component summary (MCS) mean scores were 52.82 ± 2.32 and 52.57 ± 2.93 in IPD patients, respectively, and 63.46 ± 3.65 and 66.39 ± 0.91 in OPD patients, respectively, which was significant (p < 0.0001). The QoL of patients decreased in the end stages of CKD. A significant association was observed between gender, occupation, smoking, and the stages of CKD with the QoL of the hospitalized patients. Measures must be taken to improve the QoL of these patients at all levels.