This cross-sectional study aims to assess parents’ knowledge, attitude, and practices on antibiotic use for children with URTIs symptoms in Greece in the era of the COVID-19 pandemic. We distributed a questionnaire to a random sample of parents who visited primary health care centers in Patras, Greece. Out of 412 participants, 86% believed that most infections with common cold or flu symptoms were caused by viruses, although 26.9% believed that antibiotics may prevent complications. Earache was the most common symptom for which antibiotics were needed. Most of them (69%) declare being considerably anxious about their children’s health during the COVID-19 pandemic. The majority (85%) knew that COVID-19 was of viral origin, yet half of them declared uncertain whether antibiotics were needed. All demographic characteristics, except for gender, were found to have a significant effect on parents’ knowledge, attitude, and practices on antibiotic use for URTIs and COVID-19. Factor analysis revealed six groups of parents with common characteristics associated with misuse of antibiotics. Our findings highlight the need to decrease misconceptions regarding antibiotic use by providing relevant education for parents targeting particular characteristics, especially during the COVID-19 pandemic. Continuous education of healthcare providers in the field is also of paramount importance.