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Objective: To observe the clinical efficacy of Zhi Shen Tiao Sui (regulating the mind and marrow) needling in treating depression after ischemic stroke. Methods: A total of 145 patients with depression after ischemic stroke were recruited between January 2016 and January 2018 and divided into two groups using random number table method, with 72 cases in the control group and 73 cases in the observation group. The control group received conventional treatment for ischemic stroke and medication, while the observation group was given additional Zhi Shen Tiao Sui acupuncture. The two groups were treated for 4 successive weeks. Clinical efficacy was analyzed after treatment. The neurological function pertinent scores [Hamilton depression scale (HAMD), clinical neurological deficit score (CNDS), activities of daily living (ADL), Fugl-Meyer assessment scale (FMA) and Barthel index (BI) scores], as well as the levels of cortisol (CORT) and adrenocorticotropic hormone (ACTH) were recorded in the two groups. Adverse reactions that occurred during treatment were also observed. Results: The clinical total effective rate was 82.2% in the observation group, significantly higher than 66.7% in the control group (P<0.05). After treatment, the HAMD and CNDS scores were markedly reduced in both groups (all P<0.05), and the ADL, FMA and BI scores were markedly increased (all P<0.05). The HAMD and CNDS scores were significantly lower in the observation group than in the control group after treatment (both P<0.05), and the ADL, FMA and BI scores were significantly higher in the observation group than in the control group (all P<0.05). The levels of CORT and ACTH declined significantly after treatment in the two groups (all P<0.05), and were markedly lower in the observation group than in the control group (both P<0.05). The adverse reaction rate was 2.7% in the observation group, versus 4.2% in the control group, and the between-group difference was statistically insignificant (P>0.05). Conclusion: Compared with sole use of Western medication, medication combined with Zhi Shen Tiao Sui acupuncture can promote the recovery of neurological function, down-regulate the levels of CORT and ACTH and enhance the clinical efficacy in treating patients with depression after ischemic stroke, with a relatively high safety rating.