A new and facile approach to selectively functionalize the internal and external surfaces of porous silicon (pSi) for drug delivery applications is reported. To provide a surface that is suitable for sustained drug release of the hydrophobic cancer chemotherapy drug camptothecin (CPT), the internal surfaces of pSi films were first modified with 1-dodecene. To further modify the external surface of the pSi samples, an interlayer was applied by silanization with (3-aminopropyl)triethoxysilane (APTES) following air plasma treatment. In addition, copolymers of N-(2-hydroxypropyl) acrylamide (HPAm) and N-benzophenone acrylamide (BPAm) were grafted onto the external pSi surfaces by spin-coating and UV crosslinking. Each modification step was verified using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, water contact angle (WCA) measurements, X-ray photoelectron spectroscopy (XPS) and scanning electron microscopy (SEM). In order to confirm that the air plasma treatment and silanization step only occurred on the top surface of pSi samples, confocal microscopy was employed after fluorescein isothiocyanate (FITC) conjugation. Drug release studies carried out over 17 h in PBS demonstrated that the modified pSi reservoirs released CPT continuously, while showing excellent stability. Furthermore, protein adsorption and cell attachment studies demonstrated the ability of the graft polymer layer to reduce both significantly. In combination with the biocompatible pSi substrate material, the facile modification strategy described in this study provides access to new multifunctional drug delivery systems (DDS) for applications in cancer therapy.