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Objective: The objective of this study was to compare the general and metabolic impact of single‐anastomosis duodeno‐ileal bypass with sleeve gastrectomy (SADI‐S) with Roux‐en‐Y gastric bypass (RYGB) in an obese (ob/ob) mouse model. Methods: 10‐week‐old male ob/ob mice underwent either SADI‐S, RYGB, or laparotomy surgery (Sham group). General and metabolic parameters were assessed during a 5‐week period thereafter. Results: SADI‐S induced a deeper weight loss ([mean ± SEM] −41.2% ± 3.3%) than RYGB (−5.6% ± 3.5%, p < 0.001) compared with the Sham group (+6.3% ± 1.0%, p < 0.05). A significant food restriction was observed after SADI‐S only (−31%, 117.4 ± 10.3 g vs. 170.2 ± 5.2 g of food at day 35 in Sham group mice, p < 0.001). Random‐fed glycemia and glucose tolerance were more improved after SADI‐S than RYGB. SADI‐S decreased plasma cholesterol concentration by 60% (0.49 ± 0.04 g/L vs. 1.40 ± 0.10 g/L in the Sham group at day 35, p < 0.01), significantly more than RYGB (1.04 ± 0.14 g/L, p = 0.018). Plasma sitosterol/cholesterol and campesterol/cholesterol ratios were decreased after SADI‐S, suggesting a reduced intestinal cholesterol absorption. SADI‐S increased exogenous plasma cholesterol‐D7 clearance and fecal elimination, also indicating an increased plasma cholesterol excretion. Studying a pair‐fed group demonstrated that calorie restriction alone did not explain the beneficial impact of SADI‐S. Conclusions: SADI‐S is associated with a greater improvement in lipid and glucose homeostasis than RYGB in ob/ob mice. [ABSTRACT FROM AUTHOR]