The COVID-19 outbreak has clearly shown that significant advances are required in protective clothing technology. This study presents fabrication of multifunctional polyacrylonitrile (PAN) nanofiber mats doped with titanium dioxide and Ag nanoparticles (Ag@PAN-TiO2 NFs). This multifunctional material exhibited antimicrobial properties, can self-clean under light due to its photocatalytic feature, and allows the detection of pollutants directly on NFs by surface-enhanced Raman scattering (SERS). The multi-functional mat showed a robust killing effect for E. coli and S. Aureus bacterial strains and bovine coronavirus. Additionally, the highly stable and reusable photocatalytic and self-cleaning activities of the mat were examined via the photocatalytic degradation of methylene blue (MB). The same molecule could be detected on the same platform at a concentration as low as 100 pM using SERS. This novel design integrated hotspot engineering with strategies to form multi-functional materials that emerge from antimicrobial, plasmonic, and photocatalytic properties.