Background/Objectives: Comparative real-world evidence on early body-weight changes during semaglutide and tirzepatide treatment remains limited, particularly in populations with unequal and irregularly timed follow-up. To compare longitudinal percentage changes in body weight between adults initiating semaglutide and those initiating tirzepatide and to describe changes in anthropometric measures, weight-loss responses, and exploratory metabolic outcomes. Methods: This retrospective, single-center, real-world longitudinal cohort study included adults aged ≥18 years initiating semaglutide or tirzepatide for weight management, with a body mass index (BMI) ≥30 kg/m² or ≥27 kg/m² with a weight-related comorbidity. Patients with type 2 diabetes and concomitant obesity were eligible. Participants were naïve to incretin-based therapy; pregnancy, previous bariatric surgery, and active malignancy were exclusion criteria. Anthropometric and laboratory data were extracted from clinical records. Percentage body-weight change over days 1–230 was analyzed using a linear mixed-effects model incorporating exact follow-up time and adjusting for age, sex, baseline BMI, and diabetes status. Scheduled-visit and sensitivity analyses were also performed. Results: The cohort included 184 patients: 94 (51.1%) receiving semaglutide and 90 (48.9%) receiving tirzepatide. Overall, mean age was 41.7 ± 12.0 years, baseline weight was 97.0 ± 17.9 kg, and 139 patients (75.5%) were female. The longitudinal analysis included 345 measurements from 148 patients (80.4%). The treatment-by-time interaction was significant (p = 0.002). Adjusted weight changes with semaglutide versus tirzepatide were −3.39% versus −4.44% at month 1 (p = 0.116), −8.38% versus −11.52% at month 3 (p < 0.001), and −14.40% versus −15.06% at month 6 (p = 0.699). Sensitivity analyses yielded consistent findings. Only four tirzepatide-treated patients had measurements within the month 6 visit window; therefore, the month 6 estimate for this group relied primarily on the model and requires cautious interpretation. Conclusions: Both semaglutide and tirzepatide were associated with early reductions in body weight. Tirzepatide was associated with larger model-adjusted weight loss at month 3 (between-group difference, −3.14 percentage points; 95% CI, −4.55 to −1.74; p < 0.001), whereas no statistically significant between-group difference was observed at month 1 (p = 0.116). Only four tirzepatide-treated patients had measurements within the month 6 visit window, limiting the reliability of this comparison. Longer-term comparisons require cohorts with more balanced follow-up and more observations at later time points.