Levothyroxine (LT4) is a cornerstone therapy for hypothyroidism and related thyroid disorders. Despite its efficacy, levothyroxine is highly susceptible to drug interactions and dosing errors, which can lead to suboptimal treatment outcomes or serious adverse effects. This review highlights the common drug interactions that impair LT4 absorption, including proton pump inhibitors, calcium and iron supplements, antacids, and various systemic medications. These interactions may cause elevated TSH levels and persistent hypothyroidism. Conversely, excessive LT4 dosing can result in hyperthyroid-like symptoms, thyrotoxicosis, cardiovascular complications, osteoporosis, and neuropsychiatric disturbances. Particular attention is given to mechanisms of interaction, clinical evidence, and strategies to mitigate adverse outcomes. The review emphasizes the importance of individualized dosing, patient education, and regular monitoring of thyroid function to optimize LT4 therapy and reduce the risk of adverse drug reactions.