Salvia officinalis (sage) has previously been shown both to possess in vitro cholinesterase inhibiting properties, and to enhance mnemonic performance and improve mood in healthy young participants. In this double-blind, placebo-controlled, crossover study, 30 healthy participants attended the laboratory on three separate days, 7 days apart, receiving a different treatment in counterbalanced order on each occasion (placebo, 300, 600 mg dried sage leaf). On each day mood was assessed predose and at 1 and 4 h postdose. Each mood assessment comprised completion of Bond–Lader mood scales and the State Trait Anxiety Inventory (STAI) before and after 20 min performance of the Defined Intensity Stress Simulator (DISS) computerized multitasking battery. In a concomitant investigation, an extract of the sage leaf exhibited dose-dependent, in vitro inhibition of acetylcholinesterase and, to a greater extent, butyrylcholinesterase. Both doses of sage led to improved ratings of mood in the absence of the stressor (that is, in pre-DISS mood scores) postdose, with the lower dose reducing anxiety and the higher dose increasing 'alertness', 'calmness' and 'contentedness' on the Bond–Lader mood scales. The reduced anxiety effect following the lower dose was, however, abolished by performing the DISS, with the same dose also being associated with a reduction of alertness during performance. Task performance on the DISS battery was improved for the higher dose at both postdose sessions, but reduced for the lower dose at the later testing session. The results confirm previous observations of the cholinesterase inhibiting properties of S. officinalis, and improved mood and cognitive performance following the administration of single doses to healthy young participants.