BackgroundDengue fever has been responsible for around 12 countrywide large outbreaks in Pakistan, resulting in 286,262 morbidities and 1,108 deaths. Khyber Pakhtunkhwa (KP) is the most recently impacted province. This study aimed to investigate the molecular, epidemiological, and potential elements that contribute to increasing dengue transmission patterns, and knowledge, attitude, and practice (KAP) toward dengue in KP province.MethodThis cross-sectional community-based study was conducted (June-December, 2021) in two phases. Phase I involved the epidemiological (n = 5,242) and molecular analysis of DENV in 500 randomly collected blood samples of the 2021 dengue outbreak in KP. Phase II focused on assessing dengue-KAP levels in healthy communities (n = 14,745, aged >18 years), adopting a cross-sectional clustered multistage sampling in eight districts (dengue-hotspot vs. non-hotspot) of KP. Chi-square tests and logistic regression analysis were applied.ResultsPeshawar district had the highest dengue cases (60.0%) associated with the predominant co-circulation of DENV-2 (45.8%) and DENV-3 (50.4%) serotypes. A rise in cases was reported in October (41.8%) followed by September (27.9%) and August (14.4%; p < 0.001). Males (63.7%, p < 0.001) and individuals aged 16–30 years (37.0%, p < 0.001) were highly affected. General workers (18.0%), families with a monthly income of 10,000–20,000 Pak rupees (50.5%), unmarried (71.0%), uneducated (31%), families with higher human density (>10 individuals per household), and those (29.0%) who faced power outages for more than 7/24 h were the most affected. Moreover, co-morbidities like renal failure and bronchial asthma were associated with disease severity. A community survey on KAP revealed that an average of 74, 60, and 43% of the participants demonstrated good knowledge, attitudes, and dengue preventive practices, respectively.ConclusionMultiple poor socioeconomic elements are influencing dengue fever transmission in the province. Higher KAP levels may explain the low frequency of dengue in non-hotspot districts. Our study emphasizes the need for effective and long-term public health education, strengthened vector surveillance, and expanded laboratory capacity for better diagnosis and management of dengue cases to better predict the burden and seasonality of disease in the country.