Abstract Background On August 4, 2020, Lebanon faced one of the deadliest mass casualty explosions the world has witnessed during the twenty-first century. The human and emotional tolls were heavy on attending physicians, clinical fellows, residents, interns, medical students, and registered nurses, who were working in dramatic conditions, triaging, and treating thousands of blast-related casualties. We evaluated the risk of developing post-traumatic stress disorder symptoms (PTSS), among these healthcare workers (HCWs) from different Lebanese hospitals. Methods This is a multicentered, cross-sectional study that was conducted in December 2020, using an online questionnaire that evaluated the risk of developing PTSS based on the validated self-reported PTSD-Checklist for DSM-V (PCL-5). We also explored possible correlates with the participants’ socio-demographic characteristics, job profile, mental health, and blast-related events. Results Out of 519 participants, 44% were at high risk of developing PTSS following Beirut-blast. Nurses, attending physicians, fellows, and participants who are older in age, married, or working at specific hospitals, were at a higher risk. Those identified at higher risk of PTSS were surgeons, anesthesiologists, emergency medicine doctors, or radiologists; and they were more likely to be willing to migrate; having a prior history of psychiatric medication intake for PTSD treatment, a prior history of PTSD, or a personal history of seeking mental health service. At last, the latter two parameters as well as the number of examined injuries, severe home damage, and testing positive for the COVID-19 virus during the two weeks’ period that followed the blast were found to be predictors for the development of PTSS. Conclusion Lebanese in-hospital HCWs were found to be at a high risk of developing PTSS following the Beirut-Blast, thus we recommend public health authorities to provide adequate resources to avoid the emergence of mental illnesses among these rescuers.