Levothyroxine (L-T4) is the gold standard therapy for treating hypothyroidism. Despite its widespread use, some hypothyroid patients report that L-T4 is ineffective in relieving their symptoms. Several factors may explain this issue, one of which is levothyroxine pharmacological interactions, either in “healthy” individuals due to its interactions with foods and supplements, or in patients with multiple treatments because of its variable pharmacokinetics and unique chemical characteristics. Guidelines recommend that in patients receiving levothyroxine treatment for hypothyroidism, an assessment of serum TSH should be performed within 4–8 weeks after treatment initiation, especially when using drugs that affect levothyroxine absorption or impact thyroid homeostasis. Since hypothyroidism is a common condition often accompanied by other comorbidities requiring treatment, good clinical practice requires awareness of these pharmacological interactions, which may necessitate adjusting or withdrawing specific medications and/or rapidly checking thyroid function to restore euthyroidism.