The purpose of this study was to evaluate and validate methylene blue migration from printed time–temperature indicators (TTIs) into food. It also highlights the importance of establishing regulatory measures and safety standards for food packaging, suggesting that this can contribute to improving food packaging safety. Liquid chromatography–mass spectrometry (LC-MS/MS) was used to quantify methylene blue migration in various food simulant and food matrix samples. The results show that the level of methylene blue migration varies significantly depending on the chemical properties of the food mimetic and the composition of the food matrix. The established method demonstrated a high sensitivity, with limits of detection (LODs) of 0.0019–0.0706 μg/L (kg) and limits of quantification (LOQs) of 0.0057–0.2138 μg/L (kg). This study highlights the need for a regulatory framework to mitigate the health risks associated with methylene blue in intelligent packaging systems and argues that regulatory thresholds should be set to ensure food safety and quality.