To fully investigate the diarrhea of human epidermal growth factor receptor 2 (HER2)‐targeted agents in cancer patients. The relevant studies of the randomized, controlled trials (RCTs) in cancer patients treated with HER2‐targeted agents were retrieved, and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until August 2018. Forty‐two RCTs and 21 633 patients were included. The current meta‐analysis suggested that the use of HER2‐targeted agents significantly increases the risk of developing all‐grade diarrhea (RR, 2.78; 95%CI, 2.37‐3.25; P < .00001) and high‐grade diarrhea (RR, 4.89; 95%CI, 3.09‐7.75; P < .00001). The RRs of all‐grade diarrhea and high‐grade diarrhea varied significantly according to drug type, control group, and treatment regimen. The RR of all‐grade diarrhea varied significantly according to tumor type. Afatinib and neratinib tended to associate with the highest risk of all‐grade diarrhea and high‐grade diarrhea, respectively. Trastuzumab was associated with the lowest risk of diarrhea. Breast cancer patients tended to have a higher risk of all‐grade diarrhea than patients with nonbreast cancer when receiving a HER2‐targeted agent. The available data suggested that the use of HER2‐targeted agents is associated with a significantly increased risk of diarrhea in cancer patients.