Current methods employed for the analysis of the chemical composition of solid matrices (such as plant, animal, or human tissues; soil; etc.) often require many sample treatment steps, including an extraction step with exclusively dedicated solvents. This work describes an optimized analytical setup in which the extraction of a solid sample is directly coupled to its analysis by high-performance liquid chromatography. This approach avoids (i) the use of pumps and valves other than those comprising the HPLC instrument, (ii) the use of solvents other than those of the mobile phase, and (iii) the need to stop the mobile phase flow at any time during the full analytical procedure. The compatibility of this approach with the direct analysis of fresh tissues (leaves, stems, and seeds of four plant species with dissimilar chemical compositions) was successfully demonstrated, leading to the elimination of sample preparation steps such as drying, grinding, concentration, dilution, and filtration, among others. This work describes a new, simple, and efficient green approach to minimize or eliminate sample treatment procedures. It could be easily applied for quality control of plant materials and their derived products through chromatographic fingerprints and for untargeted metabolomic investigations of solid matrices, among other applications.