A unique all-fiber interferometric sensor was proposed and successfully demonstrated efficient low-refractive-index liquid sensing in the range from 1.33 to 1.37, which is compatible with those of bio-liquids. A special silica coreless optical fiber with an open V-groove was used as an optical sensing medium, which provided a high sensitivity for a minute liquid volume in the nanoliter scale. The V-groove fiber (VGF) was serially concatenated between two single-mode fibers (SMFs). The LP₀₁ mode guided along the input SMF excited the higher-order modes in the VGF to generate multimode interference, whose spectrum was transmitted through the output SMF. A single liquid droplet with volume of ∼80 nanoliters wet the entire hydrophilic surface of the VGF, and the transmission spectra shifted corresponding to its refractive index in a very linear manner. The sensor also showed a negligible temperature cross-sensitivity in the range 25°C–75°C, which overlaps with the biological temperature window such that the sensitivity of 159.696 nm per refractive index unit (nm/RIU) remained independent of the temperature variation. Modal properties of VGF were thoroughly analyzed numerically, and detailed processes for the sensor fabrication and sensing experiments were reported.