Adverse drug reactions (ADR) are a cause of public health concern globally. Voluntary ADR reporting is the basis of pharmacovigilance program in several countries. However, underreporting of ADRs is widely known among various World Health Organization member countries, including Malaysia. Hence, this study aimed to assess the knowledge, attitudes, and practices (KAP) regarding ADR reporting among healthcare professionals in a tertiary hospital in Malaysia. A cross-sectional study was conducted using a self-administered questionnaire, which consisted of 40 items to assess the KAP regarding ADR reporting. The participants were specialists, medical officers, house officers, and nurses working at Hospital Tuanku Ja'afar, Seremban, Malaysia. Among the respondents, 56.9% of the participants had satisfactory knowledge; however, desirable practices were noted among 37.8% of the participants. Approximately one-fifth of them were found to have attitudinal barriers toward the reporting process, whereas 40.71% showed desirable attitudes toward the motivators for ADR reporting. It was also observed that professionals with greater knowledge have lesser negative attitudes and greater satisfactory practices, whereas those with greater positive attitudes have greater satisfactory practices. In conclusion, the healthcare professionals working at a tertiary healthcare center in Malaysia had satisfactory knowledge but showed poor practices due to perceived barriers toward ADR reporting processes.