Postoperative fluid overload is associated with increased mortality and morbidity in infants with congenital heart disease (CHD). Loop diuretics, such as furosemide, are commonly used to prevent fluid overload in the postoperative period. This study aimed to investigate the effect of postoperative albumin levels on the efficacy of furosemide after surgery in infants with CHD. From 1 January 2017 to 31 December 2022, postoperative albumin levels, total furosemide doses, and three-day postoperative diuresis levels were retrospectively analyzed in 186 patients aged 0–1 years who underwent cardiopulmonary bypass at the Pediatric Intensive Care Unit, Diyarbakır Gazi Yaşargil Training and Research Hospital. Demographic and clinical parameters, along with urine output in the first 6 h, first 24 h, 24–48 h, and 48–72 h postoperatively, were recorded. Patients were divided into two groups based on their albumin levels: normal albumin (≥30 g/dL) and hypoalbuminemia (<30 g/dL). A common protein interaction network for albumin and furosemide was constructed using Cytoscape software (version 3.10.2). Of the 186 patients, 79 (42.5%) were male and 107 (57.5%) were female, with a median age of 97.5 days (range 1–360 days). Furosemide doses were higher in hypoalbuminemic patients on postoperative days 1 and 2 compared to normoalbuminemic patients. On postoperative day 1, hypoalbuminemia was more prevalent in patients with oliguria, whereas normoalbuminemia was significantly higher in patients with normouria and polyuria. Furosemide doses were significantly higher in patients with oliguria than in those with normouria in the first 6 h and lower in patients with polyuria compared to those with normouria. A positive correlation was observed between albumin levels and furosemide efficacy on postoperative day 2. Additionally, a positive correlation existed between albumin levels on postoperative day 1 and urine output in the first 6 and 24 h postoperatively. Furosemide efficacy and urine output were positively correlated in the postoperative period. Mortality risk was significantly higher in hypoalbuminemic patients on postoperative days 1 and 2, as well as in patients with oliguria in the first 6 and 24 h postoperatively. Network analysis revealed that albumin was directly involved in furosemide’s target network, along with six other proteins within the common interaction network. Diuresis levels were significantly lower in hypoalbuminemic patients. We suggest that the effectiveness of furosemide is reduced because it cannot bind to albumin at sufficient levels. The effective management of albumin levels may enhance furosemide efficacy and improve postoperative outcomes in infants with CHD.