Acetaminophen is a well-known drug commonly used to provide pain relief, but it can also lead to acute liver failure at high concentrations. Therefore, there is considerable interest in monitoring its concentrations. Sensitive and selective acetaminophen electrochemical sensors were designed by cycling a glassy carbon electrode (GCE) to high potentials in the presence of β-CD in a phosphate electrolyte, or by simply activating the GCE electrode in the phosphate solution. Using cyclic voltammetry, adsorption-like voltammograms were recorded. The acetaminophen oxidation product, N-acetyl benzoquinone imine, was protected from hydrolysis, and this was attributed to the adsorption of acetaminophen at the modified GCE. The rate constants for the oxidation of acetaminophen were estimated as 4.3 × 10–3 cm2 s–1 and 3.4 × 10–3 cm2 s–1 for the β-CD-modified and -activated electrodes, respectively. Using differential pulse voltammetry, the limit of detection was calculated as 9.7 × 10–8 M with a linear concentration range extending from 0.1 to 80 μM. Furthermore, good selectivity was achieved in the presence of caffeine, ascorbic acid and aspirin, enabling the determination of acetaminophen in a commercial tablet. Similar electrochemical data were obtained for both the β-CD-modified and activated GCE surfaces, suggesting that the enhanced detection of acetaminophen is connected mainly to the activation and oxidation of the GCE. Using SEM, EDX and FTIR, no evidence was obtained to indicate that the β-CD was electropolymerised at the GCE.