Persistent chemotherapy-related cognitive impairment (CRCI) is commonly reported following cancer treatment and negatively affects quality of life. While past research has focused on potential pathophysiological mechanisms underlying this relationship, the role of psychological factors, such as mood, stress, and anxiety, in the development of persistent CRCI has received less attention. As an additional analysis of data from a trial investigating the effects of transdermal nicotine patches on cognitive performance in patients with persistent CRCI, we examined whether change in mood was associated with changes in subjective and objective cognitive functioning. Participants were randomized to either placebo (n = 11) or transdermal nicotine (n = 11) for 6 weeks, followed by 2 weeks of treatment withdrawal for a total of 8 weeks. Participants were assessed using behavioral, subjective, and objective measures of cognitive functioning and mood at five visits before, during, and after treatment. Although we did not detect an effect of treatment assignment on mood, over the course of the study, we observed a significant improvement on measures of mood that correlated with improvement in subjective and objective cognitive performance. We observed improvement in objective and subjective cognitive performance measures. These changes were associated with improvement in subsyndromal mood symptoms, likely resulting from participation in the trial itself. These results suggest that women with persistent CRCI may benefit from support and validation of their cognitive complaints, cognitive rehabilitation/therapies into their post-cancer care. The study was registered with clinicaltrials.gov (trial registration: NCT02312943). © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.