The present study was aimed at elucidation of malaria epidemiology and comparing performance of several diagnostic procedures in Bannu, a highly endemic district of Khyber Pakhtunkhwa, Pakistan. Dried blood spots were collected from patients suspected of malaria visiting a hospital and two private laboratories in district Bannu and processed for species-specific PCR (rRNA). Patients were also screened for malaria through microscopy and RDT. A well-structured questionnaire was used to collect patient information to assess risk factors for malaria. Of 2033 individuals recruited, 21.1% (N = 429) were positive for malaria by at least one method. Overall, positivity detected by PCR was 30.5% (95/311) followed by 17.7% by microscopy (359/2033) and 16.4% by RDT (266/1618). Plasmodium vivax (16.9%, N = 343) was detected as the dominant species followed by Plasmodium falciparum (2.3%, N = 47) and mixed infections (1.2%, N = 39). Microscopy and RDT (Cohen's kappa k = 0.968, p = <0.0001, McNemar test p = 0.069) displayed significant agreement with each other. Satisfactory health, sleeping indoors, presence of health-care facility in vicinity (at an accessible range from home), living in upper middle class and in concrete houses significantly reduced malaria risk; whereas, low literacy level, presence of domestic animals indoors and malaria diagnosis recommended by clinician increased the disease risk. Overall, findings from the study provide reasonable basis for use of RDT as a cost-effective screening tool in field and for clinicians who can proceed with timely treatment of malaria patients. Appropriate management of identified risk factors could contribute to reduction of malaria prevalence in Bannu and its peripheries.