<p>Monkeypox (MPOX) is a zoonotic viral disease that has re-emerged and spread to non-endemic regions, drawing global attention. Understanding the knowledge, attitudes, and practices (KAP) of vulnerable populations, particularly in conflict-affected areas, is crucial for effective public health responses. This community-based cross-sectional study evaluates the KAP of the general Syrian population regarding MPOX, focusing on areas affected by conflict. The study was conducted between October 25 and November 22, 2024, using a culturally adapted and validated structured online and paper-based questionnaire. A total of 2,035 responses were collected. The sample included predominantly female participants (63.8%), aged 21–30 years (41.9%), mostly married (73.4%), and urban residents (72.4%). Statistical analysis included confidence intervals (95%) and significance levels (<i>p</i> &lt; 0.05). The study revealed that while 80.3% of participants understood causative factors, 81.2% transmission, 89% prevention, and 78.2% symptoms, significant knowledge gaps were identified in vaccination (13.4%) and diagnostic tests (42.7%), with 58.9% of respondents demonstrating poor overall knowledge. Negative attitudes were reported in 65.8% of participants, although urban residents exhibited slightly more positive attitudes. Good practices were observed in 73.6% of respondents, with common behaviors including isolation and frequent handwashing (58.8%). However, practices did not significantly differ across genders or marital status. Higher knowledge scores were associated with males (OR = 1.721, 95% CI= [1.42–2.07]), higher education levels (OR = 1.324, 95% CI= [1.07–1.62]), and higher incomes (OR = 2.550, 95% CI= [1.56–4.15]). The conflict-affected context likely exacerbated knowledge gaps and negative attitudes, underscoring the urgent need for culturally tailored educational campaigns and public health initiatives. These efforts are critical for improving MPOX preparedness in vulnerable populations.</p>