Background: Abnormal liver blood tests (LBTs) in hyperthyroid patients are not uncommonly encountered. One major adverse event of antithyroid drug (ATD) therapy is drug-induced hepatotoxicity. Abnormal LBT in the hyperthyroidism scenario is a main diagnostic and therapeutic dilemma. We aimed to assess the prevalence and the response to ATD therapy of LBT abnormalities in newly diagnosed and uncomplicated hyperthyroidism through a systematic review and meta-analysis. Methods: A literature search was performed reporting LBTs at presentation and after ATD therapy in hyperthyroid patients. A proportion meta-analysis was performed with random-effects model. Pooled data were presented with 95% confidence intervals (CI). I ² statistic index was used to quantify the heterogeneity. Sensitivity analyses for prevalence of hyperthyroid patients with at least one abnormal LBT were performed. p -Value of <0.05 was regarded as significant. Results: The literature search yielded 2286 studies, of which 25 were included for systematic review and meta-analysis. The prevalence of untreated hyperthyroid and Graves' disease patients with at least one abnormal LBT was 55% ([CI 46–63%], I ² 96%) and 60% ([CI 53–67%], I ² 92%), respectively. The prevalence of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bilirubin (BIL), and γ-glutamyltransferase (GGT) abnormalities in hyperthyroid patients were 33% ([CI 24–44%], I ² 95%), 23% ([CI 17–29%], I ² 89%), 44% ([CI 35–52%], I ² 93%), 12% ([CI 7–20%], I ² 92%), and 24% ([CI 16–36%], I ² 95%), respectively. ATD therapy, along with euthyroidism restoration, was accompanied by normalization of LBT abnormalities in the following percentage of cases: ALT 83% ([CI 72–90%], I ² 46%), AST 87% ([CI 74–94%], I ² 2%), ALP 53% ([CI 32–73%], I ² 76%), BIL 50% (CI cannot be calculated), and GGT 70% ([CI 47–87%], I ² 74%). The sensitivity analyses showed similar results as those of the main analyses. The publication bias was not statistically significant for all outcomes, except for the prevalence of resolved BIL abnormalities that was not calculable. Conclusions: LBT abnormalities are common in newly diagnosed and untreated hyperthyroidism setting. A high chance of safely normalizing elevated transaminases, up to fivefold above the upper limit of normal, accompanies the use of ATDs in the treatment of hyperthyroidism.