Introduction: Patients with hematological malignancies undergo intensive treatment and prolonged hospitalization, thus having a variety of physical and psychosocial symptoms and worse quality of life (QOL). Aim: This study aimed to assess the QOL and investigate the symptoms of hospitalized hematological cancer patients. Methods: A cross-sectional study was conducted in the hematology clinics and day units of two general hospitals of Heraklion, Crete. Adult patients with hematological malignancy and an adequate understanding of the Greek language participated. A demographic questionnaire, the European Organization for Research and Treatment for Cancer quality assessment questionnaire (EORTC QLQ-C30), and the MD Anderson Symptom Inventory (MDASI) were used for data collection. The level of statistical significance was set at p <0.05. Results: The sample consisted of 120 patients, 42.5% of whom were women, with a mean age of 65.6 years. The mean time from diagnosis was 33 months. The global health status of QoL had an average value of 47.1. The highest levels of QOL were found in the subscale of cognitive function (72.8) and the lowest in the role function (46.1). Among the of EORTC QLQ-C30 symptoms scale, the lowest score was found in nausea-vomiting (11.0) and the highest in fatigue (59.1). In the MDASI, in part I (core symptoms), higher levels, but also medium intensities were reported at fatigue (78.3%, mean 3.5), drowsiness (65.0, mean 3.3), and distress (65.8%, mean 2.8). In part II, enjoyment of life (85.8%, mean 5.1) had the highest and relation with other people (67.5%, mean 3.7) the lowest scores. The increase in the severity of the core symptoms (part I) was related to females (rho = 0.193, p <0.05) and comorbidities (rho = 0.220, p <0.05). It also related to a significant decrease in all functional domains and an increase in fatigue (rho = 0.571, p <0.05) of the EORTC QLQ-C30 questionnaire. The increased global health status was related to males (rho = -0.185, p <0.05) and physical functioning with younger age (rho = -0.331, p <0.05), higher education (rho = 0.239, p <0.05), fewer months from diagnosis (rho = -0.199, p <0.05) and low comorbidity (rho = -0.209, p <0.05). Finally, the increased global health status was significantly related to lower symptoms determined by the total average symptom score (-0.491, p <0.05). Conclusions: The QoL of hematological cancer patients is significantly decreased during treatments due to a significant number of symptoms that must be taken into consideration for high-quality individualized care.