Background and Objectives: Acute abdominal pain in children has been noticed to be a primary reason to seek medical attention in multisystem inflammatory disorder (MIS-C), which can prevail separately or together with acute appendicitis. Our aim was to distinguish regular appendicitis cases from MIS-C and to suggest the best clinical and laboratory criteria for it. Materials and methods: Cases of patients, admitted to the Pediatric Surgery Department over a six-month period in 2021, were retrospectively analyzed. Confirmed MIS-C or acute appendicitis cases were selected. MIS-C cases were either separate/with no found inflammation in the appendix or together with acute appendicitis. Acute appendicitis cases were either regular cases or with a positive COVID-19 test. Four groups were formed and compared: A-acute appendicitis, B-MIS-C with acute appendicitis, C-MIS-C only and D-acute appendicitis with COVID-19. Results: A total of 76 cases were overall analyzed: A-36, B-6, C-29 and D-5. The most significant differences were found in duration of disease A—1.4 days, B—4.5 days, C—4 days, D—4 days (p < 0.0001), C reactive protein (CRP) values A-19.3 mg/L B-112.5 m/L, C-143.8 mg/L and D-141 mg/L (p < 0.0001), presence of febrile fever A-13.9%, B-66.7%, C-96.6% and D-40% (p < 0.0001) and other system involvement: A 0%, B 100%, C 100% and D 20%. A combination of these factors was entered into a ROC curve and was found to have a possibility to predict MIS-C in our analyzed cases (with or without acute appendicitis) with an AUC = 0.983, p < 0.0001, sensitivity of 94.3% and specificity of 92.7% when at least three criteria were met. Conclusions: MIS-C could be suspected even when clinical data and performed tests suggest acute appendicitis especially when at least three out of four signs are present: CRP > 55.8 mg, symptoms last 3 days or longer, febrile fever is present, and any kind of other system involvement is noticed, especially with a known prior recent COVID-19 contact, infection or a positive COVID-19 antibody IgG test.