Background Elevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for atherosclerotic cardiovascular disease (ASCVD). However, low adherence to medication and lifestyle management has limited the benefits of lowering lipid levels. Cognitive behavioral therapy (CBT) has been proposed as a promising solution. Objective This trial aimed to evaluate the efficacy of mobile-based CBT interventions in lowering LDL-C levels in patients with ASCVD. Methods This multicenter, prospective, randomized controlled trial enrolled 300 patients with ASCVD, who were randomly assigned to the mobile-based CBT intervention group and the control group in a ratio of 1:1. The intervention group received CBT for ASCVD lifestyle interventions delivered by WeChat MiniApp: “CBT ASCVD.” The control group only received routine health education during each follow-up. The linear regression and logistic regression analyses were used to determine the effects of a mobile-based CBT intervention on LDL-C, triglyceride, C-reactive protein, the score of General Self-Efficacy Scale (GSE), quality of life index (QL-index), and LDL-C up-to-standard rate (<1.8 mmol/L) at the first, third, and sixth months. Results Finally, 296 participants completed the 6-month follow-up (CBT group: n=148; control group: n=148). At baseline, the mean LDL-C level was 2.48 (SD 0.90) mmol/L, and the LDL-C up-to-standard rate (<1.8 mmol/L) was 21.3%. Mobile-based CBT intervention significantly increased the reduction of LDL-C change (%) at the 6-month follow-up (β=–10.026, 95% CI –18.111 to –1.940). In addition, this benefit remained when baseline LDL-C <1.8 mmol/L (β=–24.103, 95% CI –43.110 to –5.095). Logistic regression analysis showed that mobile-based CBT intervention moderately increased the LDL-C up-to-standard rates (<1.8 mmol/L) in the sixth month (odds ratio 1.579, 95% CI 0.994-2.508). For GSE and QL-index, mobile-based CBT intervention significantly increased the change of scores (%) at the 1-, 3-, and 6-month follow-up (all P values <.05). Conclusions In patients with ASCVD, mobile-based CBT is effective in reducing LDL-C levels (even for those who already had a standard LDL-C) and can improve self-efficacy and quality of life. Trial Registration Chinese Clinical Trial Registry ChiCTR2100046775; https://www.chictr.org.cn/showproj.aspx?proj=127140