Direct detection of genetic biomarkers in tissue and body fluids without complex target extraction and amplification processes can revolutionize nucleic acid-based diagnostics by enabling the use of this technology at the point-of-care. The development of point-of-care diagnostics is important to increase access to early treatment in underserved populations in low to middle income countries, which are disproportionally affected by infectious diseases and increasingly affected by certain types of cancer. The main obstacle to the development of such technologies is the low concentration of target sequences that makes this goal challenging. We report a method for direct detection of pathogen RNA in blood lysate using a bioassay using surface-enhanced Raman spectroscopy (SERS)-based detection assay that can be integrated in a “lab-in-a-stick” portable device. We could directly detect synthetic target with a limit of detection of 200 fM and, more importantly, we detected P. falciparum malaria parasite RNA directly in infected red blood cells lysate. Additionally, this paper will discuss the use of the developed assay for the identification of head and neck squamous cell carcinoma (HNSCC), which is an increasingly prevalent malignancy in low to middle income countries.