Background: Acute Myeloid Leukemia (AML) is a hematologic malignancy characterized by immune dysfunction, metabolic alterations, and physical decline, significantly impacting patient resilience, rehabilitation, and overall functional capacity. Monocyte-associated gene signatures play a crucial role in shaping the tumor microenvironment, influencing immune response, and determining patient prognosis, all of which can affect treatment efficacy and physical rehabilitation outcomes. This study aims to investigate the clinical relevance of monocyte-related genes in AML, assess their impact on the tumor microenvironment, and explore potential strategies for precision therapy and integrative rehabilitation interventions. Methods: A weighted gene co-expression network analysis (WGCNA) was performed to identify and validate a prognostic model based on monocyte-associated genes. The biological enrichment pathways, somatic mutations, immune landscape, and metabolic characteristics were analyzed in high- and low-risk AML patient subgroups. Additionally, potential disease regulatory networks, small molecule drug predictions, and drug sensitivity assessments were explored to provide insights into targeted therapy and immune-modulating interventions. Results: A four-gene monocyte-related prognostic signature (FBXL5, TIGAR, VDR, and ZCWPW1) was identified, effectively classifying AML patients into distinct risk subgroups with significant differences in clinical outcomes, immune activity, and metabolic profiles. The low-risk subgroup demonstrated a strong association with immune system activation and metabolic resilience, showing enhanced immune function, enriched biological pathways linked to immune-metabolic interactions, and a higher immune score. These findings suggest that monocyte-related gene expression is intricately linked to immune adaptation and metabolic fitness, both of which are essential for patient recovery and physical rehabilitation strategies. Conclusion: Monocyte-related gene signatures are closely associated with immune regulation, metabolic stability, and AML patient prognosis, with direct implications for precision therapy, rehabilitation, and physical resilience. These gene markers could serve as valuable prognostic biomarkers and potential therapeutic targets for immune-modulating and exercise-based interventions aimed at enhancing physical function, improving recovery outcomes, and optimizing integrative leukemia treatment protocols. Future research should explore how exercise, metabolic conditioning, and immune-targeted therapies can be incorporated into holistic rehabilitation programs to improve AML patient outcomes.