Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging treatment for medication-refractory essential tremor (ET). The objective of this study was to evaluate long-term (up to 5 years) safety and efficacy of unilateral MRgFUS in the treatment of ET. The authors performed a systematic search through 4 databases to find relevant clinical studies. Binary outcomes were analyzed and reported as odds ratios and 95% confidence intervals, while continuous outcomes were analyzed and reported as standardized mean differences (SMDs) and 95% confidence intervals. Furthermore, a univariable meta-regression was performed to evaluate the association between various covariates and the outcomes including the mean difference in the Clinical Rating Scale for Tremor (CRST) score and hand tremor scores. Sensitivity analysis was performed to address any heterogeneity. A total of 43 studies comprising 1818 patients with ET who underwent MRgFUS were identified. Of the 1539 patients with data on sex, 1095 (71.2%) were male. The mean follow-up duration ranged from 3 months to 8.4 years among the studies. The mean total CRST score significantly decreased at 3, 6, and 12 months post-MRgFUS (SMD -4.5, p = 0.0069; SMD -4.9, p = 0.0045; and SMD -2.95, p = 0.0039, respectively). The mean hand tremor scores significantly mitigated at 3, 6, 12, 24, and 36 months post-MRgFUS (SMD -3.99, p = 0.05; SMD -4.5, p = 0.05; SMD -1.99, p < 0.0001; SMD - 2.07, p = 0.0002; and SMD -2.1, p < 0.0001, respectively). Furthermore, the mean Quality of Life in Essential Tremor Questionnaire scores were improved at 3 months (SMD -2.8, p = 0.0025), 6 months (SMD -4.1, p = 0.04), 12 months (SMD -1.57, p = 0.0004), 2 years (SMD -1.64, p = 0.0003), and 3 years (SMD -1.14, p = 0.08). Our meta-regression findings showed that sex (p = 0.03), unlike age, handedness, symptom duration, and peak energy levels at 3 months, was associated with a significantly higher mean difference in tremor severity. This meta-analysis provides strong evidence supporting the efficacy and safety of unilateral MRgFUS for the treatment of ET in terms of tremor severity and quality of life with acceptable adverse events.