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). This study aimed to assess the QOL and investigate the symptoms of hospitalized hematological cancer patients. 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. The sample consisted of 120 patients—42.5% 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). For the 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) had 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 was also associated with a significant decrease in all functional domains and increased fatigue (rho = 0.571, p < 0.05) in 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, multiple linear regression analysis revealed that the total average symptom score of the MDASI was the most significant factor influencing the global health status of the EORTC QLQ-C30 (β = −4.91, p < 0.001). The increased global health status of the EORTC QLQ C30 was not significantly related (p > 0.05) to the social characteristics of the patients, such as education or employment, which requires further validation. The QoL of hematological cancer patients significantly decreases during treatments due to a considerable number of symptoms that must be taken into consideration for high-quality, individualized care.