(1) Background: Various methods to predict the presence or absence of choledocholithiasis (CDL) have been proposed. We aimed to assess the performance characteristics of dynamic liver enzyme trends in the prediction of CDL. (2) Methods: This was a single-center retrospective cohort study. All adult in-patients undergoing endoscopy for suspected CDL between 1 January 2012 and 7 October 2018 were identified, with patients with prior cholecystectomy, prior sphincterotomy, or indwelling biliary prostheses were excluded. Available laboratory parameters within 72 h preceding the procedure were recorded, allowing for the assessment of trends. Dynamic enzyme trends were defined as any increase or decrease by 30% and 50% within 72 h of the index procedure. (3) Results: A total of 878 patients were included. Mean age was 61.8 years, with 58.6% female. Increases in alkaline phosphatase (ALP) of at least 30% or 50% were both specific for the presence of CDL, with specificities of 82.7% (95% CI 69.7–91.8%) and 88.5% (95% CI 76.6–95.6%), respectively. Decreases in bilirubin or ALP of at least 50% were highly specific for the absence of CDL, with specificities of 91.7% (95% CI 85.7–95.8%) and 100.0% (97.2–100.0%), respectively. (4) Conclusions: Several liver enzyme trends appear to be specific for the absence or presence of stones; in particular, significant decreases in total bilirubin or ALP of at least 30–50% over the prior 72 h appear to be especially predictive of an absence of intraductal findings during endoscopy.