Background: To confirm effective preventive practice and reduce the risk of COVID-19 data on knowledge, attitude, and preventive practices (KAP) are essential. Therefore, the current study was designed to evaluate the KAP of COVID-19 among people with hypertension (HTN) and/or diabetes mellitus (DM) attending public health facilities in Ambo town. Patients and Methods: Institutional-based cross-sectional study design was done among patients with HTN and/or DM from June 2020 to September 2020 at Ambo University Referral Hospital (AURH) and Ambo General Hospital (AGH). To identify the associated factors with poor practice and knowledge, logistic regression analyses were used. Results: The mean age of the study respondents was 44.6 years (± 9.84) of which the majority were male 235 (55.6%) and 159 (37.59%) of the participants had good knowledge. Concerning attitude, 335 (79.2%) have strongly believed that DM and HTN patients were more at risk of death because of COVID-19. Only 44 (10.4%) of them had a good level of COVID-19 prevention practice measures. Patients who use the source of information daily were 54.4% less likely to have poor knowledge about COVID-19 than those who use it weekly. Participants with no formal education were 3 times more likely to have poor COVID-19 prevention practice than those who were with formal education, and participants who have poor knowledge about COVID-19 were 2 times more likely to have poor COVID-19 prevention practice than those who have knowledge. Conclusion: The prevalence of poor knowledge about COVID-19 was low, and only less than ¾ of the participants strongly believed COVID-19 as a serious disease. A small percentage of participants had a good level of COVID-19 prevention practice. Good knowledge had an association with a good level of prevention practice. So, health sectors should work to increase accessibility of COVID-19 information.