Interferometry　has　been　widely　used　in　biosensing　due　to　its　ability　to　acquire　molecular　affinity　and　kinetics　in　real-time.　However,　interferometric-based　sensors　are　susceptible　to　environmental　disturbances,　including　temperature　and　non-specific　binding　of　target　molecules,　which　reduces　their　detection　robustness.　To　address　this　shortcoming,　this　paper　proposes　a　self-referencing　interference　sensor　based　on　coherence　multiplexing　to　resist　environmental　disturbances.　The　proposed　sensor　can　address　temperature　and　non-specific　binding,　but　it　is　not　limited　only　to　these　types　of　disturbances.　In　the　proposed　sensor　design,　each　sensor　signal　is　encoded　using　a　specific　optical　path　difference　determined　by　the　optical　thickness　of　a　sensor　chip.　In　addition,　two　sensor　signals　for　disturbances　tracking　and　biomolecule　detection　are　detected　simultaneously　without　additional　cost　to　the　second　spectrometer　and　then　differenced　to　achieve　real-time　self-reference.　The　temperature　fluctuations　experiments　and　specific　binding　experiments　of　protein　A　to　IgG　are　performed　to　verify　the　performance　of　the　proposed　sensor.　The　results　demonstrate　that　the　proposed　sensor　can　eliminate　non-specific　binding　and　temperature　disturbances　in　real-time　during　biomolecule　detection,　achieving　higher　detection　robustness.　The　proposed　sensor　is　suitable　for　applications　that　require　large-scale　testing　of　biomolecular　interactions,　such　as　drug　screening.