Aim: To compare the proportion of adverse events reports associated with levothyroxine versus other medications and between high-dose (≥100 μg) and low-dose (<100 μg) levothyroxine. A disproportionality analysis was conducted using data from FAERS individual case safety reports (2004–2023) via OpenFDA, with levothyroxine and comparator drugs as primary suspects. Methods: Disproportionality analysis was performed using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-Item Gamma Poisson Shrinker (MGPS). Signals required confirmation by all four criteria (i.e., IC025 > 0, the lower bound of RR and PRR > 1, and EGBM05 > 2) . Dose-dependent signals were identified using ROR, PRR, and IC025.. Levothyroxine-associated AEs were identified using MedDRA-v27.1 preferred term. Results: Analysis of 45,877 FAERS reports identified 201,473 levothyroxine-related Adverse events and 291 safety signals when comparing levothyroxine with other drugs. Among these, 22 signals were labeled (e.g., irritability [ROR: 13.49], palpitations [ROR: 13.29], alopecia [ROR: 10.25]), while 269 were unexpected (e.g., polyglandular autoimmune syndrome type II [ROR: 118.76], social avoidant behavior [ROR: 48.49]). In a comparison between high-dose (≥100 μg) and low-dose (<100 μg) levothyroxine, 21 signals were identified, including acute kidney injury (ROR: 4.69), increased blood triglycerides (ROR: 3.67), and malabsorption (ROR: 2.90). Conclusions: This study outlines levothyroxine’s safety profile, highlighting both known and unexpected adverse events, with evidence of dose-dependent risks between high- and low-dose levothyroxine. Further pharmacoepidemiologic research is needed to confirm these findings and investigate the underlying mechanisms.