Highly sensitive, simple and multiplex detection capabilities are key criteria of point-of-care (POC) diagnosis in clinical samples. Here, a simple and highly sensitive multi-analyte detection technique is proposed by using photonic crystal fiber (PCF) based surface plasmon resonance (SPR) sensor that employs both internal and external sensing approaches. The proposed sensor can detect two different analytes simultaneously by the internal and external plasmonic micro-channels. The light propagation through the sensor is controlled by the scaled-down air-holes to excite the free electrons of the plasmonic metal layers. The light- guiding and sensing properties of the sensor is numerically analyzed by using the Finite Element Method (FEM). The proposed sensor shows the maximum wavelength sensitivities (WS) of 12,000 nm/refractive index unit (RIU), and 10,000 nm/RIU, for the internal and external sensing approaches, respectively, and corresponding resolution of 8.33×10−6 RIU and 1.0×10−5 RIU. Moreover, the hybrid sensor is applicable to detect unknown analyte refractive index (RI) in the range of 1.33 to 1.40 which covers extensively investigating analytes such as viruses, different cancer cells, glucose, proteins and DNA/RNA. Due to high sensing performance with multi-analyte detection capability, the proposed sensor can play a significant role to detect bio targets at the POC platform.