The use of norepinephrine and the restriction of intraoperative hydration have gained increasing acceptance over the last few decades. Recently, there have been concerns regarding the impact of this approach on renal function. The objective of this study was to examine the influence of norepinephrine, intraoperative fluid administration and their interaction on acute kidney injury (AKI) after cystectomy. In our cohort of 1488 consecutive patients scheduled for cystectomies and urinary diversions, the overall incidence of AKI was 21.6% (95%—CI: 19.6% to 23.8%) and increased by an average of 0.6% (95%—CI: 0.1% to 1.1%,p= 0.025) per year since 2000. The fluid and vasopressor regimes were characterized by an annual decrease in fluid balance (−0.24 mL·kg−1·h−1, 95%—CI: −0.26 to −0.22,p< 0.001) and an annual increase in the amount of norepinephrine of 0.002 µg·kg−1·min−1(95%—CI: 0.0016 to 0.0024,p< 0.001). The interaction between the fluid balance and norepinephrine levels resulted in a U-shaped association with the risk of AKI; however, the magnitude and shape depended on the reference categories of confounders (age and BMI). We conclude that decreased intraoperative fluid balance combined with increased norepinephrine administration was associated with an increased risk of AKI. However, other potential drivers of the observed increase in AKI incidence need to be further investigated in the future.