Background/Objectives: Rising antimicrobial resistance threatens Helicobacter pylori eradication worldwide, yet real-world data on microbiologically confirmed treatment outcomes from the Middle East remain scarce. This study aimed to determine the confirmed eradication failure rate among treatment-naïve patients, identify independent predictors of failure, and characterize gaps in post-treatment testing practices. Methods: This retrospective cohort study included treatment-naïve adults diagnosed with H. pylori infection at King Abdulaziz Medical City in Riyadh between January 2015 and August 2023. The primary outcome was microbiologically confirmed eradication failure, defined exclusively as a positive post-treatment test of cure (urea breath test, stool antigen, or endoscopic biopsy). Exploratory logistic regression was used to identify factors associated with treatment failure. Results: Of 850 patients, 196 (23.1%) had a documented post-treatment eradication test. The confirmed failure rate was 33.7% (66/196). In multivariate analysis, atrophic gastritis (aOR 3.22, 95% CI: 1.29–8.02; p = 0.012) and pregnancy (aOR 12.76, 95% CI: 1.79–91.06; p = 0.011) were independently associated with failure. No treatment regimen was significantly associated with eradication outcome. Conclusions: One in three tested patients failed first-line eradication, and over three-quarters of treated patients never received a confirmatory test of cure. These findings support transitioning to bismuth-based quadruple therapy in line with current guidelines and local resistance data, mandating routine post-treatment eradication testing, and establishing antimicrobial susceptibility surveillance.