The aim of this paper is to measure the knowledge and attitudes of primary care physicians toward antibiotic prescriptions and their impacts on antibiotic prescribing. A questionnaire survey was conducted on 625 physicians from 67 primary care facilities in Hubei, China. Structural equation modelling (SEM) was applied to test the theoretical framework derived from the Knowledge, Attitudes, and Practices (KAP) theory. Physicians’ knowledge, five sub-types of attitudes, and three sub-types of behavioral intentions towards antibiotic use were measured. Physicians had limited knowledge about antibiotic prescriptions (average 54.55% correct answers to 11 questions). Although they were generally concerned about antibiotic resistance (mean = 1.28, SD = 0.43), and were reluctant to be submissive to pressures from consumer demands for antibiotics (mean = 1.29, SD = 0.65) and the requirements of defensive practice (mean = 1.11, SD = 0.63), there was a lack of motivation to change prescribing practices (mean = −0.29, SD = 0.70) and strong agreement that other stakeholders should take the responsibility (mean = −1.15, SD = 0.45). The SEM results showed that poor knowledge, unawareness of antibiotic resistance, and limited motivation to change contributed to physicians’ high antibiotics prescriptions (p < 0.001). To curb antibiotic over-prescriptions, improving knowledge itself is not enough. The lack of motivation of physicians to change needs to be addressed through a systematic approach.