Epinephrine is a naturally occurring Catecholamine neurotransmitter, playing a key role in the fight-orflight response in the body. Surface Enhanced Raman Spectroscopy (SERS) is regarded as an ideal detection technique due to its specificity and sensitivity. Here, we report the experimental SERS detection of Epinephrine solution down to 10 μM using a simple, inexpensive A4-paper-based substrate coated with silver nanoparticles. We also perform Density Functional Theory (DFT) calculations of the Epinephrine molecule in the presence of small silver clusters Agn (n = 1-4) to understand the chemical interactions between the molecule and the clusters. It is observed that there are two different minima for the Epinephrine-Ag4 complexes; one of these shows an increase in the calculated Raman activity, and the other shows an increase in the stability, with increasing number of atoms in the silver cluster. These observations are further investigated and explained through the calculation of the interaction energies, reactivity parameters, electrostatic properties and Natural Bond Orbital (NBO) analysis.