Continuous monitoring of drug dynamics directly in living tissue remains a major challenge, notably in the brain, where the blood-brain barrier creates distinct microenvironments. Here, we report an implantable fiber optic surface plasmon resonance (FO-SPR) biosensor coated with aptagel, a split-aptamer-crosslinked hydrogel, for continuous monitoring of a small-molecule drug, vancomycin. The aptagel undergoes analyte-induced volumetric and refractive index changes, providing a self-contained means for reversible, label-free optical detection via shifts in the SPR wavelength (λSPR) while ensuring sensor stability in complex physiological matrices. The sensing area was miniaturized to 3 mm2 (3 mm length, 300 μm diameter) for cortical implantation while maintaining sensitivity of >2000 nm/RIU. The sensor performed consistently in vitro across diverse biological media, including blood serum, with detection limits of 1.7-2.5 μM. Upon implantation into the rat cortex, time-resolved λSPR signals were recorded over several hours after intravenous vancomycin administration, representing to our knowledge the first demonstration of plasmonic fiber-based monitoring of a small-molecule drug directly in brain tissue. Baseline-corrected shifts (ΔλSPR) captured in vivo drug dynamics, with a consistent absorption phase but with inter-animal variability in peak amplitude and clearance kinetics. This work establishes a proof-of-concept platform for continuous optical monitoring in deep tissue and highlights the potential of FO-SPR sensing for in vivo pharmacokinetic applications.