Recently, analytical separation techniques have the potential toward green approaches to reduce the environmental impact. This study focuses on the development of an analytical method for the determination of paracetamol and chlorzoxazone in their pharmaceutical combination. The separation was achieved using a home-made capillary column (0.10 mm i.d. × 200 mm length) filled with porous cross-linked hexyl polymethacrylate as monolithic stationary phase. The method proved to be simple, fast, sensitive, efficient, cost-effective and green approach due to the combination of the amazing properties of a monolithic material and a miniaturized liquid chromatography, which would be considered as a step toward reducing the analytical costs and the environmental impact of chromatographic applications. Both components were detected using a 3-nL nano-UV cell fixed at 270 nm wavelength. The optimized mobile phase was composed of 1% aqueous formic acid solution and acetonitrile at 40:60 ratio, 1.0 μL/min flow rate, 4.0 nL injection volume and 50°C column temperature. Under the optimized conditions, paracetamol and chlorzoxazone have been separated in about 6.5 min with chromatographic resolution of 2.37. The prepared column and the analysis method was fully validated and compared with other reported works. All findings allow to conclude that the prepared column and proposed method are applicable for quality control and routine analysis of the two drugs.