Background: Adenomyosis is a gynecological benign lesion caused by the invasion of endometrium and stroma into normal myometrium. To further improve the treatment of adenomyosis, the objective of this study was to investigate the clinical effect of levonorgestrel-releasing intrauterine system, combined with gonadotropin-releasing hormone agonist (GnRH-a) drug-assisted focused ultrasound ablation, in the treatment of adenomyosis and its effect on phosphatidylinositol 3 kinase/phosphatase and tensin homolog (PI3K/PTEN) signal pathway. Methods: A study was conducted in subjects aged 28–54 years with adenomyosis, treated in our hospital. A total of 87 subjects were assigned to a control group (n = 41), which was given focused ultrasound ablation, and a study group (n = 46), which was given focused ultrasound ablation + GnRH-a + levonorgestrel-releasing intrauterine system, depending on the different treatment methods. The follow-up time was 12 months, and the treatment effect, adverse reaction, and PI3K/PTEN signal pathway related protein level were compared between the two groups. Results: After 12 months intervention, it was corroborated significant difference between focused ultrasound ablation group and the focused ultrasound ablation + GnRH-a + levonorgestrel group in uterine volume, visual analogue scale (VAS) score, pictorial blood loss assessment chart (PBAC) score, and serum cancer antigen 125 (CA125) levels. In terms of proteins level in the eutopic endometrial tissue, it was observed notably higher levels of PTEN and notably lower levels of protein kinase B (AKT) and p-AKT in the study group versus control group, 12 months after treatment. Conclusions: Levonorgestrel-releasing intrauterine system combined with GnRH-a drug-assisted focused ultrasound ablation is more effective in the treatment of adenomyosis, and its mechanism may be related to the regulation of the expression of molecules related to PI3K/PTEN signal pathway.