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Background Cardiovascular disease (CVD) is a leading cause of death worldwide, and hyperlipidemia is a significant risk factor for CVD. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as an important target for lipid-lowering therapy and CVD prevention. Objective To investigate the differences in blood lipid levels among Han, Uyghur, Kazakh, Hui, and Mongolian ethnic groups in Xinjiang after treatment with PCSK9 inhibitors and to explore ethnic variations. Methods This retrospective cohort study included 4 167 patients with hyperlipidemia from Han, Uyghur, Kazakh, Hui, and Mongolian ethnic groups who were hospitalized in the Heart Center of the First Affiliated Hospital of Xinjiang Medical University between April 2019 and May 2024 and received evolocumab or alirocumab for lipid-lowering therapy for more than 4 weeks. Baseline data were collected, and multiple linear regression analysis was used to explore the correlation between ethnicity and blood lipids in different categories of hyperlipidemia patients. Results A total of 2 634 Han patients (63.2%), 1 027 Uyghur patients (24.6%), 218 Kazakh patients (5.2%), 251 Hui patients (6.0%), and 37 Mongolian patients (1.0%) were included. Statistically significant differences were observed among Han, Uyghur, Kazakh, Hui, and Mongolian patients in terms of gender, body weight, BMI, education level, smoking, alcohol consumption, hypertension, aspartate aminotransferase (AST), total bilirubin, use of statins, ezetimibe, proportion of PCSK9 inhibitor use, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) (P<0.05). Multiple linear regression analysis showed that after treatment with PCSK9 inhibitors, Uyghur patients had 4.713% and 11.173% higher TC and LDL-C levels, respectively, and 6.889% lower HDL-C levels compared to Han patients (P<0.05). Kazakh patients had 5.925%, 5.925%, and 12.720% higher TC, HDL-C, and LDL-C levels, respectively, and 23.792% lower TG levels compared to Han patients (P<0.05). Mongolian patients had 14.025% higher TC levels compared to Han patients (P<0.05). After treatment with evolocumab, Uyghur patients had 5.196% and 11.173% higher TC and LDL-C levels, respectively, and 4.720% lower HDL-C levels compared to Han patients (P<0.05). Kazakh patients had 7.399%, 5.925%, and 17.220% higher TC, HDL-C, and LDL-C levels, respectively, and 25.011% lower TG levels compared to Han patients (P<0.05). Hui patients had 1.599% lower HDL-C levels compared to Han patients (P<0.05), while Mongolian patients had 21.899% and 13.240% higher TC and HDL-C levels, respectively, compared to Han patients (P<0.05). After treatment with alirocumab, Uyghur patients had 10.662% higher LDL-C levels and 12.502% lower HDL-C levels compared to Han patients (P<0.05). Stratified analysis by age and gender showed that male patients treated with PCSK9 inhibitors had 4.472% and 10.917% higher TC and LDL-C levels, respectively, and 6.675% lower HDL-C levels in Uyghur patients compared to Han patients (P<0.05). Kazakh patients had 4.713% higher HDL-C levels and 26.549% lower TG levels compared to Han patients (P<0.05). Hui patients had 4.940% lower HDL-C levels compared to Han patients (P<0.05). Female patients treated with PCSK9 inhibitors had 9.648% higher LDL-C levels and 8.589% lower HDL-C levels in Uyghur patients compared to Han patients (P<0.05). Kazakh patients had 11.173% higher TC levels compared to Han patients (P<0.05). In patients younger than 60 years treated with PCSK9 inhibitors, Uyghur patients had 6.905% and 15.878% higher TC and LDL-C levels, respectively, and 5.811% lower HDL-C levels compared to Han patients (P<0.05). Kazakh patients had 16.145% higher LDL-C levels and 28.879% lower TG levels compared to Han patients (P<0.05). There were no statistically significant differences in TC, TG, HDL-C, and LDL-C levels between Hui and Han patients (P>0.05). Mongolian patients had 17.761% higher TC levels compared to Han patients (P<0.05). In patients 60 years and older treated with PCSK9 inhibitors, Uyghur patients had 8.167% lower HDL-C levels compared to Han patients (P<0.05). Kazakh patients had 6.905% higher HDL-C levels and 17.965% lower TG levels compared to Han patients (P<0.05). Conclusion After treatment with PCSK9 inhibitors, Uyghur patients had higher TC and LDL-C levels and lower HDL-C levels compared to Han patients. Kazakh patients had higher TC, HDL-C, and LDL-C levels and lower TG levels compared to Han patients. There were no significant differences in TC, TG, HDL-C, and LDL-C levels between Hui and Han patients. Mongolian patients had higher TC levels compared to Han patients.