Objective <p>Cancer-related fatigue is highly prevalent among cancer patients. This study aimed to evaluate the effects of acupuncture on fatigue levels and quality of life in breast cancer patients with cancer-related fatigue.</p> Methods <p>This pilot study employed a double-center, randomized, single-blind, placebo-controlled design. A total of 68 breast cancer patients with cancer-related fatigue who fulfilled the inclusion criteria were recruited and randomly allocated into either an acupuncture group (<i>n</i> = 34) or a sham acupuncture group (<i>n</i> = 34). Both groups selected the same acupoints: CV12, CV4, CV6, LI4 (bilaterally), KI3 (bilaterally), ST36 (bilaterally), and SP6 (bilaterally). The acupuncture group employed traditional acupuncture techniques to insert needles into the acupoints to elicit the deqi sensation. By contrast, the sham acupuncture group utilized blunt needles that did not penetrate the skin. Both groups underwent a 6-week treatment regimen consisting of 20 sessions (4 sessions per week during weeks 1–3 (approximately every other day) and a total of 8 sessions during weeks 4–6 (2–3 sessions per week, every 2–3 days), each lasting 30&#xa0;min). Changes in scores on the brief fatigue inventory (BFI), fatigue scale-14 (FS-14), and hospital anxiety and depression scale (HADS) were assessed at week 0, 6, 8, and 10. Additionally, compliance with and safety of acupuncture were documented. Research variables between the two groups were compared using a significance level of <i>p</i> &lt; 0.05.</p> Results <p>The study revealed a time-dependent therapeutic advantage of acupuncture over sham acupuncture. While both groups showed similar short-term reductions in fatigue (BFI: acupuncture 6.69 ± 1.66 vs. sham acupuncture 6.19 ± 1.60; between-group <i>p</i> = 0.223) and psychological distress at week 6 after treatment, acupuncture demonstrated progressively amplified benefits. During the 10-week follow-up period, acupuncture achieved significantly greater reductions in fatigue severity (BFI: Δ = -1.28, <i>p</i> = 0.011; FS-14: Δ = -1.81, <i>p</i> = 0.003) and psychological symptoms (HADS-A: Δ = -2.06, <i>p</i> = 0.006; HADS-D: Δ = -1.81, <i>p</i> = 0.003), with intergroup differences widening over time (week 8 vs. week 10). Both groups exhibited full compliance, and acupuncture-related adverse events were limited to mild ecchymosis (9.4%). These findings suggest acupuncture induces time-dependent modulation beyond placebo effects.</p> Conclusion <p>Acupuncture can sustainably and effectively alleviate fatigue symptoms in cancer patients, improve their anxiety and depressive symptoms, and demonstrate high safety and compliance.</p> Trial registration <p>This clinical trial was prospectively registered in the Chinese Clinical Trial Registry (ChiCTR2300069361; 14/03/2023) (<a href="https://www.chictr.org.cn/">https://www.chictr.org.cn/</a>).</p>