Objective: To investigate the efficacy of transcutaneous electrical nerve stimulation (TENS) combined with drug therapy for endometriosis (EM)-related chronic pelvic pain (CPP) and its influence on the TGF-β/Smads signaling pathway. Methods: 78 patients with endometriosis-associated CPP were enrolled and divided into two groups according to different treatment regimens. The control group (n=39) received routine drug intervention, while the observation group (n=39) received TENS treatment in addition to the treatment of the control group. The treatment course for both groups was 2 months. Clinical efficacy, quality of life [Endometriosis Health Profile-5 (EHP-5)], anal sphincter muscle ultrasound indicators [levator hiatus (LH) anteroposterior diameter (AP), area (A), left-right diameter (LR)], levels of inflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1)], stress hormones [norepinephrine (NE), cortisol (Cor)], pain mediators [substance P (SP), β-endorphin (β-EP), 5-hydroxytryptamine (5-HT), prostaglandin E2 (PGE2)], TGF-β/Smads signaling pathway expression levels, and the incidence of adverse reactions during treatment were compared between the two groups. Results: The treatment efficacy rate in the observation group was higher than that in the control group (P<0.05). After treatment, the EHP-5 scores in the observation group were lower than those in the control group (P<0.05). The increases in LH AP, LH LR, and LH A indices in the observation group were greater than those in the control group (P<0.05), and the serum levels of IL-6, TNF-α, MCP-1, Cor, and NE were decreased (P<0.05). The levels of SP, PGE2, and 5-HT in the observation group were lower than those in the control group (P<0.05), while the concentration of β-EP was higher than that in the control group (P<0.05). The expression of TGF-β1 mRNA and Smad3 mRNA in peripheral blood mononuclear cells of the observation group were lower than those in the control group (P<0.05), while Smad7 mRNA was higher (P<0.05). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). Conclusion: TENS combined with drug therapy for EM-related CPP can effectively alleviate pain symptoms, improve the quality of life, promote the recovery of pelvic floor function, regulate inflammation and stress responses, and modulate TGF-β/Smads signaling pathway expression.