Background: Levothyroxine (LT4) is widely prescribed, often for subclinical hypothyroidism (SCH), despite limited evidence of clinical benefit in patients without overt hypothyroidism. This updated systematic review synthesizes current evidence on biochemical, symptom, and safety outcomes following thyroid hormone (TH) discontinuation. Methods: In this systematic review, electronic databases were searched from inception to September 25, 2026, for randomized controlled trials (RCTs) and observational studies evaluating supervised TH discontinuation. Primary outcomes included postdiscontinuation thyroid function, symptom changes, adverse events, and need for therapy reinitiation. Random-effects meta-analyses estimated pooled proportions and mean differences. Results: Twenty-three studies met inclusion criteria (22 observational studies, 1 RCT), most evaluating LT4 monotherapy discontinuation ( n = 20). Twenty-one studies including 2020 participants reported categorical TH status outcomes; 37% of participants (CI, 26%–48%; I 2 = 94.5%) remained euthyroid after discontinuation. Euthyroidism was less frequent among patients with initial overt hypothyroidism (11%, CI, 2%–38%) than among those with SCH (41%, CI, 21%–65%). Eleven studies (1104 participants) reported TH reinitiation, with 60% of patients restarting therapy (CI, 39%–78%; I 2 = 97.1%) in the overall population, increasing to 87% (CI, 66%–96%) among those with overt hypothyroidism. Thyroid autoantibody positivity, heterogeneous thyroid ultrasound findings, and higher baseline TSH levels were associated with therapy reinitiation. Thyroid-related symptoms after discontinuation were generally unchanged, and adverse events were uncommon. Conclusions: Approximately 37% of patients remained euthyroid after TH discontinuation, with higher success rates among those initially treated for SCH. These findings support consideration of deprescribing in selected patients, particularly those without clear indications for treatment initiation, using a structured approach with close biochemical monitoring and predefined criteria for therapy reinitiation.