Kidney surgery often includes organ ischemia with risk of acute kidney injury. The present study tested if treatment with combined angiotensin II-AT1 receptor and neprilysin blocker Entresto® (LCZ696-sacubitril/valsartan) protects filtration barrier and kidney function after ischemia and partial nephrectomy in pigs. Single kidney glomerular filtration rate (GFR) by technetium-99m-diethylene-triamine-pentaasetate ([99mTc]Tc-DTPA) clearance was validated (n = 6). Next, four groups of pigs were followed for 15 days (n = 24) after: 1) Partial nephrectomy (1/3 right kidney, 60 min ischemia) + Entresto® (49/51 mg/day, n = 8); 2) partial nephrectomy + vehicle (n = 8); 3) sham + Entresto® (49/51 mg/day, n = 4); 4) sham + vehicle (n = 4). GFR, diuresis, and u-albumin were measured at baseline and from each kidney after 15 days. The sum of single kidney GFR (25 ± 6 mL/min, right and 31 ± 7 mL/min, left) accounted for total GFR (56 ± 14 mL/min). Entresto® had no effect on baseline blood pressure, p-creatinine, midregional pro atrial natriuretic peptide (MR-proANP), heart rate, and diuresis. After 15 days, Entresto® increased GFR in the uninjured kidney (+23 ± 6 mL/min, P < 0.05) and reduced albuminuria from both kidneys. In the sham group, plasma MR-proANP was not altered by Entresto®; it increased to similar levels 2 hours after surgery with and without Entresto®. Fractional sodium excretion increased by Entresto®. Kidney histology and kidney injury molecule-1 in cortex tissue were not different. In conclusion, Entresto® protects the filtration barrier and increases the functional adaptive response of the uninjured kidney.