Background <p>We aimed to compare upper endoscopy (UE) with histopathology (biopsy) for detecting reflux-related findings at 1 and 3 years following one-anastomosis gastric bypass (OAGB).</p> Methods <p>This retrospective analysis included 150 OAGB patients. UE (macroscopic) and biopsy (microscopic) findings were collected from the distal esophagus, gastric pouch, and anastomotic site. Five diagnostic indices—sensitivity, specificity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve—were calculated to assess UE relative to biopsy.</p> Results <p>The mean age was 34.7 ± 11.4 years; 75.3% were female. At the distal esophagus, normal UE findings increased from 75.7% at year 1 to 92.7% at year 3 (odds ratio [OR] = 0.32, <i>p</i> = 0.005). Gastric pouch abnormalities rose from 57.6% to 73.4% (OR = 2.03, <i>p</i> = 0.007). Anastomotic site abnormalities increased from 16.0% to 21.7% (OR = 1.46, <i>p</i> = 0.226). Biopsy findings for the distal esophagus showed a nonsignificant increase in abnormalities (OR = 1.54, <i>p</i> = 0.103), whereas gastric pouch abnormalities rose significantly (OR = 3.45, <i>p</i> &lt; 0.001). Diagnostic accuracy varied by anatomical region and follow-up interval. UE reliably detected but poorly excluded distal esophageal disease. At the gastric pouch, UE could both identify and rule out disease with high accuracy. At the anastomotic site, UE findings closely mirrored biopsy results, making it a potential substitute when biopsy is unavailable.</p> Conclusions <p>Longer-term follow-up is needed post-OAGB. While UE effectively identifies distal esophageal disease, it may yield false negatives. By contrast, UE at the gastric pouch and anastomotic site reliably detects or excludes disease, offering a viable alternative to biopsy. Research of UE’s diagnostic accuracy at various time points in post-OAGB populations is required.</p>