Chronic pain represents one of the most important public health problems, with a great prevalence of comorbidity with depression and cognitive decline. Antidepressants such as duloxetine, a serotonin-norepinephrine reuptake inhibitor, represent an essential part of the therapeutic strategy for chronic pain management in addition to classical analgesics. Duloxetine is endowed with good efficacy and a good profile of safety and tolerability. Yet, duloxetine is metabolized by the cytochrome P450 system 2D6 and 1A2 (CYP2D6 and CYP1A2) and it exhibits moderate inhibitory activity on CYP2D6, resulting in side effects and metabolic interactions that may occur on a long term therapeutic schedule. Cyclodextrins (CyDs) are used in pharmaceutical applications for numerous purposes, including the improvement of drug bioavailability. In order to evaluate their effects on the activity of duloxetine, we first spectrophotometrically studied the host-guest complexes obtained combining duloxetine and different β-CyD derivatives (β-CyD, β-CyDen-c-(Glu-Glu), and succinyl-β-CyD) and then performed in vivo and in vitro studies. Among duloxetine/CyDs complexes, succinyl-β-CyD ameliorated the analgesic activity of duloxetine in the tail flick test and in the formalin test in mice and significantly protected the drug from CYP2D6 metabolism.