Background: Psychological disorders are prevalent in patients having undergone gastrointestinal cancer surgery, and their emotional status may further deteriorate during subsequent chemotherapy. Psychobiotics are specific probiotics that have the unique characteristics of producing neuroactive substances that are thought to act on the brain–gut axis. The aim of the present study was to evaluate the benefits of a psychobiotic formula on depression and anxiety status, as well as on perceived stress, versus a placebo in patients on a chemotherapy course following gastrointestinal surgery for cancer. Patients: The enrolled patients, allocated to the psychobiotic and placebo groups, were assessed by means of these psychometric tests: Beck’s Depression Inventory and the Hamilton Depression Rating 17-item Scale for depression; the General Anxiety Disorder-7 for anxiety; and the Perceived Stress Scale-14 Item for perceived stress at three time-points: upon allocation [T1], after one month of treatment [T2], and two months thereafter [T3]. Results: In total, 266 patients were included. One month of psychobiotic treatment improved [i] depression status by 60.4% [48 depressed patients at T1, reduced to 16 at T3]; [ii] anxiety by 57.0% [72 patients at T1, 26 at T3]; and [iii] stress by 60.4% [42 at T1, 14 at T3]. The placebo-treated patients experienced a deterioration in all parameters studied, i.e., depression increased by 62.9%, anxiety by 39.7%, and stress by 142.5%. Conclusions: Based on these findings, it can be recognized that psychobiotic treatment has great potential for every patient at risk of suffering from depression, anxiety, or stress during the course of surgery/chemotherapy for gastrointestinal cancer.