Background: The diagnosis of celiac disease (CD) has been substantially improved with the availability of highly sensitive CD-specific IgA-TG2, Ig-GDP, and IgA-EMA. The European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) published (2012) and updated (2020) diagnostic criteria for CD in order to simplify CD diagnosis and to avoid biopsies in selected patients. Methods: A prospective study including 5641 pediatric patients (0–16 years old) from January 2012 to January 2019 was performed. CD diagnosis was made according to the ESPGHAN algorithm. The objective of this study was to evaluate the utility of biomarkers and the relationship between TGA-IgA and EMA titers. Results: CD diagnoses were confirmed in 113 patients, 110 were IgA-TG2-positive and 3 (2.7%) had IgA deficiency. The diagnosis was made by serologic tests in 95 (84.1%) patients. Only 18 (15.9%) patients underwent intestinal biopsy. We obtained 100% concordance between IgA-EMA and positive results for IgA-TG2 ≥ 10 ULN with IgA-EMA antibody titer ≥ 1:80. Conclusions: This study provides evidence of a positive correlation between IgA-TG2 antibody serum levels and IgA-EMA. The diagnosis could be guaranteed with strict application of IgA-TG2 values ≥ 10 ULN (confirmed by subsequent testing) plus the serological response to the gluten-free diet (GFD).