Background: Levothyroxine (LT4) therapy is highly effective for biochemical correction of hypothyroidism, yet many patients report persistent symptoms and reduced health-related quality of life (HRQoL) despite achieving target thyroid-stimulating hormone (TSH) levels. Whether alternative management strategies meaningfully improve HRQoL remains clinically important. Aim: To systematically review and qualitatively synthesize evidence on the relationship between hypothyroidism management approaches and patient quality of life. Methods: A systematic review was performed following PRISMA principles. Eligible studies were primary clinical studies evaluating adults with hypothyroidism or subclinical hypothyroidism in which HRQoL was measured and related to a management approach, treatment strategy, formulation, or biochemical response. Nine studies met eligibility and were synthesized qualitatively due to heterogeneity in populations, interventions, comparators, and HRQoL instruments. Results: Evidence from large randomized trials in older adults with subclinical hypothyroidism showed no clinically meaningful HRQoL benefit from LT4 compared with placebo or usual care. In primary hypothyroidism, switching from LT4 tablets to liquid LT4 was consistently associated with improved patient-reported QoL in selected cohorts, often without major changes in thyroid biochemistry. Trials of LT4/LT3 combination therapy generally did not demonstrate consistent HRQoL superiority over LT4 alone, although some studies reported patient preference or selective domain improvements. Observational studies and surveys repeatedly documented impaired HRQoL among LT4-treated patients compared with controls, and HRQoL was frequently weakly correlated or not correlated with TSH/FT4 within the reference range. Conclusion: Quality of life in treated hypothyroidism is influenced by more than biochemical normalization alone. LT4 treatment in older adults with subclinical hypothyroidism does not appear to improve HRQoL, while liquid LT4 may improve HRQoL in selected, dissatisfied, or absorption-challenged patients. Combination therapy remains an inconsistent strategy for HRQoL improvement. Future research should prioritize patient-centered outcomes, identify phenotypes of persistent symptoms, and test targeted management pathways using validated thyroid-specific HRQoL instruments.