Background <p>The World Health Organization recommends integrating the safety monitoring of herbal medicines into existing pharmacovigilance (PV) systems to avoid overburdening the healthcare systems and national PV centres. However, there are few reports (0.3%) of herbal medicine Adverse Drug Reactions (ADRs) in the global database originating from Africa. An efficient PV system requires the involvement and commitment of healthcare professionals since they are primary contacts in transferring safety information from patients and consumers to national regulatory authorities (NRAs).</p> Objectives <p>The aim of this study was to determine the healthcare professionals’ knowledge, attitudes and practices regarding PV and herbal medicine safety in Tanzania.</p> Methods <p>An observational, cross-sectional, multicentre study was conducted in five regions of Tanzania, involving healthcare professionals working in pharmacies, hospitals, health centres, dispensaries and accredited drug dispensing outlets. Researcher-administered questionnaires were used.</p> Results <p>A total of 380 healthcare professionals participated in the study. The findings showed the majority of the healthcare professionals (65.8%) scored low on knowledge of PV and herbal medicines ADRs (62.9%). Although most respondents (86.8%) expressed favourable attitudes towards ADR reporting, this did not translate into practice, as only a small proportion (22.9%) actively reported ADRs to the NRA, with only 18.4% of the submitted case reports composed of herbal medicines. Most healthcare professionals (70.8%) perceived herbal medicines to be safer than conventional medicines. ADR reports lacked important information for causality assessment and signal identification by the NRA. Reports included all herbal products regardless of their source or origin. Professional background was a significant predictor of knowledge of PV (<i>p</i> &lt; 0.001) and herbal medicines ADRs (<i>p</i> &lt; 0.001). Pharmacovigilance training and the availability of ADR reporting forms were found to play a significant role in ADR reporting practices (<i>p</i> &lt; 0.001).</p> Conclusions <p>The study revealed several gaps in the knowledge, attitudes and practices of healthcare professionals in PV and herbal medicines safety monitoring that require several interventions. Targeted efforts are required to promote knowledge and awareness of pharmacovigilance, herbal medicines and their safety to healthcare professionals at all healthcare system levels.</p>