This study aimed to ascertain the diagnostic accuracy of CA125, HE4, systemic immune-inflammation index (SII), fibrinogen-to-albumin ratio (FAR), prognostic nutritional index (PNI), and their combination for ovarian cancer (OC) to discover an optimal combined diagnostic index for early diagnosis of OC. A thorough investigation was conducted to ascertain the correlation between these markers and the pathological characteristics of OC, thereby providing a foundation for early identification and treatment of this disorder. One hundred seventy patients with documented OC and benign ovarian tumors (BOTs) treated at Hebei General Hospital between January 2019 and December 2022 were included in this retrospective study. Data analysis was conducted using IBM SPSS Statistics version V26.0, MedCalc Statistical Software version 19.4.0, and the R Environment for Statistical Computing software (R Foundation for Statistical Computing). Isolated CA125 showed the best application value for differentiating benign ovarian tumors from OC when the defined variables were compared separately. The combination of CA125, HE4, FAR, SII, and PNI displayed a greater area under the operating characteristic curve curve than any one of them or other combinations of the 5 variables. Compared to CA125 alone, the combination of CA125, HE4, FAR, SII, and PNI showed a slight gain in sensitivity (83.91%), negative predictive value (83.91%), accuracy (85.88%), and a decrease in negative likelihood ratio (0.180%). Higher preoperative CA125, HE4, SII, and FAR levels, and lower PNI levels predicted a higher probability of advanced OC progression and lymph node metastasis. FAR has better application value than other inflammation-related markers (PNI and SII). This study suggests that preoperative serum SII, PNI, and FAR may be clinically valuable markers in patients with OC. FAR has better application value than other inflammation-related markers (PNI and SII). As we delve deeper into the inflammatory mechanisms associated with tumors, we may discover more effective combinations of tumor and inflammatory biomarkers.