Cost-effective health care technologies for detection of disease biomarkers at ultralow concentrations can significantly improve the quality of life in resource-constrained countries. However, current techniques require expensive instruments, complex conjugation protocols and tedious laboratory procedures that may not be affordable for the major part of the world population. Here, we propose to sidestep the problem by establishing a simple, relatively inexpensive sensing method employing a photonic substrate, a material affinity peptide, and a smart phone CCD detector to achieve detection of clinically relevant proteins in serum at concentrations much lower than standard enzyme-linked immunosorbent assay (ELISA). Easy to process porous silicon (PSi) micro-cavities were employed as substrates that provide a three-dimensionality, large surface area, and convenient light enhancement properties for molecular detection. Anti-histone H2B antibodies and biomarkers of severe illnesses are detected in whole serum at concentrations as low as 10 fg mL−1 by using the proposed PSi-ELISA protocol. Due to its easy use, cost effectiveness and high sensitivity, the proposed method has potential large- scale applications in ultrasensitive sensing of different other clinically relevant molecules for early stage diagnostics.