Background: The diagnosis of acute appendicitis (AA) remains challenging, especially in pediatrics, because early symptoms are not specific, and the younger the patient the more difficult their interpretation is. There is a large degree of agreement between pediatric surgeons on the importance of an early diagnosis to avoid complicated acute appendicitis (CAA) and its consequences. The aim of this study is to assess if Interleukin 6 (IL-6) could enhance the sensitivity (Sn) and specificity (Sp) of the currently available and routinely performed diagnostic tools in case of suspected AA in pediatric patients. Materials and Methods: A prospective observational study was conducted including patients who underwent appendectomy between November 2020 and March 2022. We divided patients into three groups: not inflamed appendix (group NA), not complicated AA (group NCAA), and complicated AA (group CAA). We compared the mean values of white blood cells (WBC), neutrophils, fibrinogen, ferritin, aPTT, INR, C-reactive protein (CRP), IL-6, and CRP between the three groups. Then we evaluated Sn, Sp, and odds ratio (OR) of IL-6 and CRP alone and combined. Results: We enrolled 107 patients operated on for AA (22 in Group NA, 63 in Group NCAA, and 21 in group CAA). CRP levels resulted in a significant increase when comparing CAA with NA (p = 0.01) and CAA with NCAA (p = 0.01), whereas no significance was found between NA and NCAA (p = 0.38). A statistically significant increase in average IL-6 levels was found when comparing NCAA with NA (p = 0.04), CAA with NA (p = 0.04), and CAA with NCAA (p = 0.02). Considering CRP alone, its Sn, Sp, and OR in distinguishing NA from AA (both NCAA and CAA together) are 86%, 35%, and 33,17, respectively. Similarly, Sn, Sp, and OR of IL-6 alone are 82%, 54%, and 56, respectively. Combining CRP and IL-6 serum levels together, the Sn increases drastically to 100% with an Sp of 40% and OR of 77. Conclusions: Our study may suggest an important role of IL-6 in the detection of AA in its early stage, especially when coupled with CRP.