Background Acute appendicitis (AA) is one of the most frequent causes of abdominal pain requiring emergency intervention in adults. Approximately one-third of cases present with atypical clinical symptoms. This study aims to compare the monocyte-to-lymphocyte ratio (MLR), red cell distribution width (RDW) to lymphocyte ratio (RLR), and systemic immune inflammation index (SII) with other biomarkers in distinguishing patients with and without AA. Methodology A total of 347 patients (AA 125, nonspecific abdominal pain 90, and control group 132) were enrolled in the study according to the cross-sectional study design. Receiver operating characteristic (ROC) analysis was used to determine the cutoff in diagnostic value measurements. Statistical significance was determined by the statistics of sensitivity, specificity, positive predictive value, and negative predictive value. Comparison of ROC curves of C-reactive protein (CRP), white blood cell (WBC), neutrophil count (NEU), neutrophil-to-lymphocyte ratio (NLR), MLR, and SII was evaluated with the pairwise comparison of ROC curves and 95% confidence interval. Results In detecting AA, CRP, WBC, NEU, NLR, MLR, and SII have excellent diagnostic power (area under the curve [AUC] 0.80-0.88), while RDW, lymphocyte count, monocyte (MON) count, and RLR had acceptable diagnostic power (AUC 0.70-0.77). When the power in the diagnosis of AA was compared, a significant difference was found between CRP and NEU, CRP and SII, WBC and NEU, and WBC and SII. Conclusions The diagnosis of AA remains dependent on many factors. Inflammatory biomarkers assist this process. MLR and SII may be recommended to use in diagnosing AA in adults, along with other clinical findings. RLR is adequate but not superior.