PCSK9 inhibitors (PCSK9i) are monoclonal antibodies that have been shown to be effective in reducing both LDL cholesterol (LDL-C) values and major cardiovascular events in patients at high cardiovascular risk. Adherence to PCSK9i is critical for the success of the treatment. The aim of the present study is to evaluate patients’ adherence to PCSK9i during the COVID-19 pandemic. Patients referred to the Cardiac Diagnostic Unit of the University of Campania “Luigi Vanvitelli” Naples, taking PCSK9i, and who missed the cardiological follow-up visit during the first national COVID-19 lockdown (9 March–17 May 2020), were included. Each patient underwent medical teleconsultation to collect current clinical conditions, adherence to drug treatments, and lipid profile laboratory tests. Among 151 eligible patients, 20 were excluded for missing or untraceable telephone numbers and one for refusing to join the interview. The selected study population consisted of 130 patients (64 ± 9 years, 68% males), of whom 11 (8.5%) reported a temporary interruption of the PCSK-9 therapy for a mean period of 65 ± 1.5 days. The non-adherent patients showed a marked increase in LDL-C than in the pre-pandemic period (90.8 ± 6.0 vs. 54.4 ± 7.7 mg/dL, p < 0.0001), and 82% of patients moved out of the LDL-C therapeutic range. The non-adherent group was more likely to have a very high cardiovascular risk compared to the adherent group (81.8 vs. 33.6%, p < 0.001). Causes of interruption included drug prescription failure (63.6%) due to temporary interruption of the non-urgent outpatient visits and failure in drug withdrawal (36.4%) due to patients’ fear of becoming infected during the pandemic. The COVID-19 lockdown caused a remarkable lack of adherence to PCSK9i therapy, risking negative implications for the health status of patients at high cardiovascular risk. Facilitating patients’ access to PCSK9i and enhancing telemedicine seem to be effective strategies to ensure the continuity of care and appropriate management of these patients.