Ghana’s rate of reporting adverse drug reaction (ADRs) over the past years has consistently been below the WHO standard despite utilizing the spontaneous or voluntary reporting system. While underreporting undermines the pharmacovigilance system and poses a huge threat to public health safety, there is limited information on the perspectives of healthcare workers directly involved in drug administration. The present study investigated the knowledge, attitude and practice of physicians and nurses at the Cape Coast Teaching Hospital (CCTH) towards spontaneous reporting of ADRs (SR-ADRs). A descriptive cross-sectional survey was employed in the study. Pre-tested (Cronbach’s alpha value of 0.72) and validated questionnaires comprising 37 open-ended and close-ended questions were administered to 44 doctors and 116 nurses at the CCTH who had been practicing for at least six months prior to study. Out of the 160 administered questionnaires, 86 was administered face-to-face and the remaining via e-mails. Descriptive analysis was performed and the results were presented in simple frequencies and percentages. Binary logistic regression model was used to test association of the independent variables with SR-ADRs. With a response rate of 86.4% for physicians and 59.5% for nurses, 38 (35.5%) physicians and 69 (64.5%) nurses completed the questionnaires and returned same. Majority (82.3%, 88) of the respondents knew that it is their responsibility to report ADRs although their knowledge levels was found to be inadequate (that is ≤80%) in majority (66.7%) of the text items that assessed knowledge levels. On the attitude of respondents, it was found that 57% (61) of them agreed that under-reporting was due to complacency whereas 80.4% (86) of them agreed that it was due the lack of adequate training. On the issues of practice, the prevalence of encountering, assisting in the management, and reporting of ADRs were 26.1% (28), 17.8% (19) and 7.5% (8) respectively. Also, nurses were 1.22 times more likely to encounter a patient with ADRs and twice more likely to fill and forward ADR form than doctors during management. Respondents with more than six months but less than one year of practice experience were more likely (AOR = 1.38, 95% CI: 2.72–7.3) to encounter a patient with ADRs as compared to those with just six months of practice experience. Furthermore, male respondents were more likely (AOR = 2.42, 95% CI: 1–5.85) to encounter patients with ADRs but less likely (AOR = 0.49, 95% CI: 0.91–2.6) to fill and forward ADR form compared to their female counterparts. In conclusion, doctors and nurses at the CCTH had inadequate knowledge about ADRs and its existing pharmacovigilance systems, thus accounting for the low spontaneous ADRs reporting in the facility.