A hollow-core metal-cladding waveguide (HCMW) optofluidic resonator that works based on a free-space coupling technique is designed. An HCMW can excite ultra-high-order modes (UOMs) at the coupled angle, which can be used as an optofluidic resonator to detect alterations of the epidermal growth factor receptor (EGFR) concentration. Theoretical analysis shows that the UOMs excited in the HCMW have a highly sensitive response to the refractive index (RI) variation of the guiding layer. An EGFR solution with a 0.2 ng/mL alteration is detected, and the RI variation caused by the concentration alteration is about 2.5×10 3.