Background The burden of the COVID-19 pandemic in Peru has led to people seeking alternative treatments as preventives and treatment options such as medicinal plants. This study aimed to assess factors associated with the use of medicinal plants as preventive or treatment of respiratory symptom related to COVID-19 during the pandemic in Cusco, Peru. Method A web-based cross-sectional study was conducted on general public (20- to 70-year-old) from August 31 to September 20, 2020. Data were collected using a structured questionnaire via Google Forms, it consisted of an 11-item questionnaire that was developed and validated by expert judgment using Aiken's V (Aiken's V > 0.9). Both descriptive statistics and bivariate followed by multivariable logistic regression analyses were conducted to assess factors associated with the use of medicinal plants for COVID-19 prevention and respiratory symptom treatment during the pandemic. Prevalence ratios (PR) with 95% Confidence Interval (CI), and a P-value of 0.05 was used to determine statistical significance. Results A total of 1,747 respondents participated in the study, 80.2% reported that they used medicinal plants as preventives, while 71% reported that they used them to treat respiratory symptoms. At least, 24% of respondents used medicinal plants when presenting with two or more respiratory symptoms, while at least 11% used plants for malaise. For treatment or prevention, the multivariate analysis showed that most respondents used eucalyptus (p < 0.001 for both), ginger (p < 0.022 for both), spiked pepper (p < 0.003 for both), garlic (p = 0.023 for prevention), and chamomile (p = 0.011 for treatment). The respondents with COVID-19 (p < 0.001), at older ages (p = 0.046), and with a family member or friend who had COVID-19 (p < 0.001) used more plants for prevention. However, the respondents with technical or higher education used less plants for treatment (p < 0.001). Conclusion There was a significant use of medicinal plants for both prevention and treatment, which was associated with several population characteristics and whether respondents had COVID-19.