Background: The distinct epidemiological patterns and host immune responses between influenza A and B viruses during co-circulation periods remain insufficiently characterized, particularly in adult populations in East Asia. This study aimed to delineate subtype-specific differences and evaluate hematological biomarkers for clinical differentiation during the 2023–2024 influenza seasons in Shanghai. Methods: We conducted a retrospective analysis of 3,270 adult influenza-like illness (ILI) cases at a Shanghai tertiary hospital fever clinic (November 2023-February 2024). Influenza A/B were confirmed by rapid antigen testing (6.67% and 2.94% positivity, respectively), and compared with healthy controls. Hematological parameters including white blood cells (WBC), neutrophils (NEUT), lymphocytes (LY), monocytes (MONO), and C-reactive protein (CRP) were analyzed using receiver operating characteristic curve (ROC) analysis and Spearman correlation. Results: Influenza A demonstrated bimodal seasonal peaks with stronger inflammatory responses, including elevated WBC, NEUT, MONO, and CRP levels along with decreased LY counts (all P < 0.05 versus controls). In contrast, influenza B exhibited unimodal circulation with 2-month delayed peaks and attenuated hematological changes. Subtype comparisons revealed significantly higher WBC, NEUT and CRP in influenza A (all P < 0.05 versus influenza B). The combined biomarker panel (WBC+NEUT+LY+MONO+CRP) achieved near-perfect discrimination (AUC: 0.9988 [95% CI: 0.9968–1.000] for influenza A, 0.9952 [0.9871–1.000] for B), outperforming individual markers. Immune network analysis identified coordinated LY-MONO-CRP interactions in influenza A versus isolated LY-MONO correlations in influenza B. Conclusions: The study reveals distinct subtype-specific patterns, with the biomarker panel enabling rapid clinical differentiation to guide management during co-circulation.