Background: Kidney transplantation is considered the first-choice therapy in end-stage renal disease (ESRD) patients. Despite recent improvements in terms of outcomes and graft survival in recipients, postoperative complications still concern the health-care providers involved in the management of those patients. Particularly challenging are cardiovascular complications. Perioperative goal-directed fluid-therapy (PGDT) and hemodynamic optimization are widely used in high-risk surgical patients and are associated with a significant reduction in postoperative complication rates and length of stay (LOS). The aim of this work is to compare the effects of perioperative goal-directed therapy (PGDT) with conventional fluid therapy (CFT) and to determine whether there are any differences in major postoperative complications rates and delayed graft function (DGF) outcomes. Methods: Prospective study with historical controls. Two groups, a PGDT and a CFT group, were used: The stroke volume (SV) optimization protocol was applied for the PGDT group throughout the procedure. Conventional fluid therapy with fluids titration at a central venous pressure (CVP) of 8–12 mmHg and mean arterial pressure (MAP) >80 mmHg was applied to the control group. Postoperative data collection including vital signs, weight, urinary output, serum creatinine, blood urea nitrogen, serum potassium, and assessment of volemic status and the signs and symptoms of major postoperative complications occurred at 24 h, 72 h, 7 days, and 30 days after transplantation. Results: Among the 66 patients enrolled (33 for each group) similar physical characteristics were proved. Good functional recovery was evident in 92% of the CFT group, 98% of the PGDT group, and 94% of total patients. The statistical analysis showed a difference in postoperative complications as follows: Significant reduction of cardiovascular complications and DGF episodes (p < 0.05), and surgical complications (p < 0.01). There were no significant differences in pulmonary or other complications. Conclusions: PGDT and SV optimization effectively influenced the rate of major postoperative complications, reducing the overall morbidity and thus the mortality in patients receiving kidney transplantation.