Standard therapy for patients with hypothyroidism is replacement with synthetic thyroxine (T4). However, thyroxine plus triiodothyronine (T3) replacement therapy resulted in marked improvements in several items of the Profile of Mood States and in a few indices of psychometric function and quality of life. The adequacy of thyroxine alone versus thyroxine plus triiodothyronine to treat hypothyroidism has yielded conflicting results. Therefore, we conducted a systematic review of all included published, randomized controlled trials to evaluate the effects of thyroxine alone or thyroxine plus triiodothyronine replacement therapy for hypothyroidism. We electronically searched Medline, Embase, the Cochrane Library, and China National Infrastructure. We also manually searched the Chinese Journal of Isotopes, Radiologia pratica, and the Chinese Journal of Endocrinology and Metabolism. A total of 10 randomized, double-blind trials (six crossovers, four parallel trials) were identified. Pooled analyses were suggestive of a statistically significant increase of free and total triiodothyronine, significant decrease of serum-free and total thyroxine in patients treated with thyroxine plus triiodothyronine, weighted mean difference (WMD) 0.03, −31.25, 2.19, 3.00; 95% confidence interval (CI) −0.14 to 0.20, −47.04 to −15.47, 0.46–3.92, 1.64–4.36, respectively. Thyroxin alone indicated significant benefits for psychological or physical well-being in terms of the General Health Questionnaire-28 (WMD: −2.90; 95% CI: −3.18 to −2.63), general health (WMD: −0.38; 95% CI: −0.71 to −0.05), physical component summary (WMD: 0.7; 95% CI: 0.53–0.87), and mental component summary (WMD: 0.58; 95% CI: 0.25–0.75); physical functioning (WMD: 1.60; 95% CI: 1.29–1.90), role–physical test (WMD: 3.60; 95% CI: 2.66–4.54), bodily pain (WMD: 2.50; 95% CI: 2.11–2.88), role–emotional (WMD: 2.08; 95% CI: 1.17–2.99), mental health (WMD: 1.30; 95% CI: 0.97–1.64) in items of the Short Form-36 Health Survey; general well-being in items of the Thyroid Symptom Questionnaire (WMD: −1.90; 95% CI: −2.48 to −1.32); better performance in the Letter Number Sequencing-working memory test in items of cognitive performance scores (WMD: 1.10; 95% CI: 0.08–2.13), significant treatment effect for blurred vision, aches, and pain (WMD: −4.66, −0.80; 95% CI: −5.339 to −4.00, −1.34 to −0.26, respectively). However, T4 plus T3 replacement improved cognitive performance (WMD: −0.49; 95% CI: −0.90 to −0.08). No significant statistical differences were found in biochemical variables, mood states clinical variables, adverse effects, and drop-out. In subgroup analysis, two included studies examined the relationship between mental improvement and causes of hypothyroidism, autoimmune, and nonautoimmune hypothyroidism, respectively. T4 alone suggested significantly higher total T4 (autoimmune and nonautoimmune thyroid, WMD: 4.5, 3.7; 95% CI: 2.24–6.76, 1.66–5.74, respectively), and significantly decreased thyroid-stimulating hormone (WMD: −0.05; 95% CI: −0.09 to −0.01). Statistically significant improvement occurred in pairs correctly recalled in the Digit Symbol Test for T4 plus T3 replacement (WMD: −1.60; 95% CI: −2.97 to −0.23) for nonautoimmune thyroid. In conclusion, on the basis of data from recent studies, we conclude that combined T4 and T3 treatment does not improve well-being, cognitive function, or quality of life compared with T4 alone. T4 alone may be beneficial in improving psychological or physical well-being. According to the current evidence, T4 alone replacement may remain the drug of choice for hypothyroid patients.