Although probiotics have been shown to improve several mental-related diseases, their association with post-stroke depression (PSD) remains unclear. This research aimed to investigate the effect of combined live Bifidobacterium, Lactobacillus, Enterococcus and Bacillus cereus tablets on PSD and serum inflammatory factors. A total of 400 stroke patients treated from January 2020 to March 2022 in Shuyang Hospital were included and randomly divided into two groups: The observation group (n = 200) and the control group (n = 200). The control group was treated with conventional therapy, while the observation group was given combined live Bifidobacterium, Lactobacillus, Enterococcus and Bacillus cereus tablets on the basis of conventional therapy. The Hamilton Depression Scale score was used to assess the degree and incidence of depression in the two groups. Recurrence and complications of PSD in stroke patients after treatment were followed up. In addition, ELISA (enzyme-linked immunosorbent assay) was employed for the detection of serum levels of nuclear factor kappa light chain enhancer of activated B cells (NF-κB), interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and logistics regression analysis was also performed for the correlation between the occurrence of PSD and NF-κB, IL-1β, and TNF-α levels. The analysis of clinical baseline data showed that the two groups of patients were comparable. After treatment, the Hamilton Depression Scale score in the observation group was significantly lower than in the control group (p < 0.05), and the observation group had a lower incidence rate of PSD, follow-up recurrence rate and complications (p < 0.05). In addition, the observation group showed a significant decrease in the serum levels of NF-κB, IL-1β and TNF-α compared with the control group (p < 0.05). Further logistics regression analysis indicated that the levels of NF-κB (OR (odds ratio) = 3.337, p < 0.001), IL-1β (OR = 2.411, p < 0.001) and TNF-α (OR = 1.557, p < 0.001) were risk factors for the development of PSD. Combined live Bifidobacterium, Lactobacillus, Enterococcus and Bacillus cereus tablets can promote neurological recovery and remission of depression in stroke patients. Such effects may be achieved by regulating the levels of NF-κB, IL-1β and TNF-α.