Background <p>Infectious mononucleosis (IM) may lead to severe complications and present diagnostic challenges in certain clinical settings. This study aimed to preliminarily evaluate the clinical utility of novel CBC-derived graphical and numerical indicators as potential tools for rapid, accurate early diagnosis and monitoring of IM in children.</p> Methods <p>A total of 204 pediatric patients with IM, exhibiting a favorable prognosis, 109 pediatric patients diagnosed with other infectious diseases, and 86 healthy controls were enrolled from the Third Affiliated Hospital of Zhengzhou University. Multiple complete blood count (CBC)-derived indicators—including the machine learning-based “IM” flag, high-fluorescence lymphocyte percentage (HFLC%), and platelet-to-lymphocyte ratio (PLR)—were analyzed at initial diagnosis and on days 7, 14, and 21.</p> Results <p>The “IM” flag, HFLC%, and PLR were independent predictors of IM (all <i>P</i> &lt; 0.01). The “IM” flag and PLR demonstrated high diagnostic efficacy across all pediatric age groups, while HFLC% showed significant diagnostic utility specifically in children over 72 months (all <i>P</i> &lt; 0.001). Optimal diagnostic cutoff values were 1.95 for HFLC% and 46.35 for PLR. During follow-up, the “IM” flag gradually turned negative within 7 days (<i>P</i><i> &lt; 0.017</i>), HFLC% decreased significantly (all <i>P</i> &lt; 0.01), whereas PLR levels showed a progressively increasing trend over 14 days (all <i>P</i> &lt; 0.001).</p> Conclusions <p>The “IM” flag, HFLC%, and PLR demonstrate significant diagnostic and prognostic value in pediatric IM, supporting their potential for clinical application.</p>