Background and Objectives: Hematological diseases can cause lasting physical and social impairments. Illness perception and emotional functioning, influenced by stigmatization and optimism, may shape these outcomes, yet their combined effects on health-related quality of life remain underexplored. This study investigates their direct and indirect links with physical and social functioning. Materials and Methods: Ninety-six hematology patients completed the EORTC QoL Scale, the Brief Illness Perception Questionnaire, the Stigma Scale for Chronic Illness, and the Revised Life Orientation Test. Analyses were performed using SPSS 25.0 software using descriptive statistics, correlations and path analysis. Results: The results indicated that more negative illness perception indirectly affected physical functioning through role (β = 0.38, p < 0.01) and cognitive functioning (β = 0.21, p < 0.05). Emotional functioning indirectly influenced social functioning via illness perception (β = -0.23, p < 0.05) and stigmatization (β = -0.34, p < 0.01), moderated by optimism. Additionally, illness perception directly predicted physical functioning (β = -0.21, p < 0.05), while emotional functioning directly predicted social functioning (β = -0.37, p < 0.01).; Conclusions: Illness perception and emotional functioning play a crucial role in shaping physical and social functioning among hematology patients. Optimism moderates these relationships, suggesting that supportive care efforts should target not only improving patients' perceptions and emotional well-being but also fostering optimism to enhance overall health-related quality of life.