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Introduction The aim was to present effective approaches utilizing novel hematological parameters for early diagnosis of juvenile-onset systemic lupus erythematosus (jSLE). Material and methods Our study at Ümraniye Training and Research Hospital involved a jSLE patient cohort from 2016 to 2022 and matched healthy controls aligning with sex and age. We use the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) for disease activity. Our approach was to analyze leukocyte, neutrophil, lymphocyte, monocyte, and platelet counts, along with ratios such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and monocyte-to-platelet ratio (MPR). We also explored novel indices: the systemic inflammatory index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) to identify relationships between systemic indices and jSLE activity. Results Upon comparative analysis with the healthy control group, systemic lupus erythematosus (SLE) patients exhibited significantly elevated levels of the hematological parameters NLR, SII, and SIRI ( p -values: 0.010, 0.048, 0.025, respectively). Among SLE patients, neutrophil, lymphocyte, and platelet distribution width (PDW) values were notably higher, while hemoglobin, red blood cell distribution width (RDW), and procalcitonin (PCT) values were significantly lower. In comparison, C-reactive protein (CRP) and sedimentation values were markedly elevated in the SLE group in contrast to the healthy control cohort. Patients with significantly elevated disease activity had notably higher values of NLR ( p = 0.010) and SII ( p = 0.048). Among patients with positive anti-nuclear antibodies (ANA), elevated levels of NLR, SII, and SIRI were noted ( p -values: 0.018, 0.021, 0.035). Conclusions In this study, the novel hematological markers SII, SIRI, and AISI were found to effectively reflect inflammation in SLE patients, exhibit associations with high disease activity, and demonstrate heightened sensitivity in detecting cases with high disease activity.