Fentanyl　and　its　derivatives　have　been　mainstays　for　the　treatment　of　pain　for　many　years.　To　accurately　detect　them　in　medical　applications　and　customs,　a　rapid,　sensitive,　and　selective　method　is　urgently　needed.　In　this　study,　we　established　a　point-of-care-testing　(POCT)　differential　Raman　approach　for　the　detection　of　fentanyl　substances　in　liquid　and　solid　conditions.　The　silver　nanoparticle　was　prepared　and　characterized　as　SERS　substrate,　which　can　adsorb　fentanyl-related　molecules　on　the　rough　surface　to　enhance　the　Raman　signal.　Subsequently,　27　kinds　of　fentanyl-related　substances　were　detected　to　determine　that　the　POCT　spectral　resolution　is　better　than　6　cm-1,　Raman　detection　range　is　100-3200　cm-1,　and　the　detection　limit　of　the　fentanyl-related　substances　at　1002　cm-1　is　0.1-25　ppb.　Furthermore,　the　Raman　characteristic　peaks　of　fentanyl　were　checked　through　comparison　between　theoretical　calculations　and　experiments　to　obtain　a　database　for　rapid　on-site　inspection.　Thus,　the　fast,　accurate,　stable　POCT　approach　can　be　widely　applied　to　monitor　drugs　and　toxins　due　to　its　sensitivity,　specificity,　and　abundance　database.