Background: Efgartigimod is a neonatal Fc receptor (FcRn) antagonist that reduces pathogenic IgG and improves clinical symptoms in generalized myasthenia gravis (gMG). However, its immunomodulatory effects on innate and adaptive immune cells beyond IgG depletion are rarely reported. Objective: This study aimed to investigate clinical and immunological responses during the initial treatment cycle of efgartigimod in naive acetylcholine receptor antibody-positive (AChR-Ab+) gMG patients, with a focus on peripheral immune cell dynamics. Methods: We conducted a longitudinal study between October 23, 2023, and December 10, 2024, based on the database of the Clinical Cohort Study of Myasthenia Gravis at Xuanwu Hospital, Capital Medical University. Seventeen naive AChR-Ab+ gMG patients were enrolled after applying strict inclusion and exclusion criteria and received a four-dose regimen of efgartigimod. Clinical efficacy was evaluated using Myasthenia Gravis Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) scores. Serum total IgG and AChR antibody levels were measured. Peripheral immune cell profiling included leukocytes, neutrophils, monocytes, platelets, and natural killer (NK) cells, as well as T and B cell subsets analyzed by flow cytometry. Longitudinal changes were assessed using linear mixed-effects models. Results: All patients achieved clinical improvement, accompanied by significant reductions in serum total IgG and AChR antibody levels. Neutrophil and leukocyte counts progressively increased and peaked at Week 3 (p < 0.05), whereas monocyte and platelet counts remained relatively stable throughout all visits. CD4+ and CD8+ T cells decreased transiently at Week 2 and partially recovered by Week 3 (p = 0.091 and p = 0.005). The CD4/CD8 ratio remained stable. NK cells showed a temporary decrease at Week 2 with a borderline significant time effect (p = 0.050), followed by partial recovery. Plasmablast proportions significantly increased at Week 2 (p < 0.05), with a parallel trend in memory B cells. A transient increase in regulatory T cells was observed at Week 1 (p < 0.05). Similar immune changes were observed in sensitivity analysis without corticosteroid use. Conclusion: This study provides the first longitudinal evidence of dynamic changes in innate and adaptive immune compartments during efgartigimod therapy in naive gMG patients. Beyond IgG clearance, efgartigimod might exert targeted immunoregulatory effects on neutrophils and lymphocyte subsets. These findings offer new insights into the broader immunological impact of FcRn-targeted therapy in gMG and underscore the need for further mechanistic and functional studies.