Mass Casualty Incidents recently increased in intensity and frequency at an unprecedented rate globally. On August 4, 2020, a massive blast hit the Port of Beirut severely damaging its healthcare sector. This study aims to provide a comprehensive understanding of the impact of the Beirut blast on acute care hospitals in the Beirut area, with a focus on understanding healthcare professionals’ (HCPs) responses and encountered challenges. A qualitative research design method was adopted to evaluate the experiences of HCPs at acute hospitals located within 5 kilometers of the blast epicenter. 9 hospitals participated in the study. 11 semi-structured interviews were conducted with key informant HCPs using a designed interview guide. HCPs reported severe infrastructural damages in their corresponding hospitals, and 2 were completely non-functional post-blast. Other than physical injuries sustained by HCPs, the blast imposed substantial strains on their mental health, exacerbated by the ongoing socio-economic crises in Lebanon. Moreover, the findings revealed critical challenges which hindered hospitals’ emergency responses at the level of communication, coordination, and human resources, as well as supplies. Participants urged for the need to conduct proper triage, arrange emergency operating centers, and deploy outdoor treatment tents among others, to effectively respond to future disasters. The Beirut blast overwhelmed the Lebanese healthcare system and challenged its level of emergency preparedness. This generated evidence to address the deficiencies and strengthen the existing hospitals’ emergency response plans. Future efforts should include prioritizing hospitals’ emergency preparedness to ensure the provision of care at increased capacity following the impact of a large-scale disaster.