Background: Although shigellosis is self-limiting, antibiotics are recommended to minimize the severity of symptoms and reduce mortality rates. However, due to the increasing reports of antibiotic resistance, alternative approaches are needed to combat shigellosis. Interest for research on medicinal plants has increased in recent years, and hence, they can be explored to treat this infectious diarrhoea. Objective: To study the effect of Psidium guajava L. (guava) leaf decoction (GLD) on the antibiotic-resistant clinical isolates of Shigella spp. Materials and Methods: A total of 43 isolated Shigella spp. from diarrhoeal patients were used in this study. The effect of GLD on the bacterial viability was initially assessed. The isolates were divided into two categories: sensitive and resistant to GLD. For sensitive isolates, antibacterial activity of GLD was evaluated while for resistant strains, the ability of GLD for reducing the bacterial invasion of the HEp-2 cell line underwent an investigation. Results: Among the 43 Shigella isolates, GLD affected the growth of 23 strains. The invasion of 9 strains from the 20 remaining resistant isolates was unaffected. Although the number of isolates was less, the data suggested that isolates belonging to S. flexneri serogroup were more sensitive to GLD in comparison with other spp (i.e., sonnei, boydii, and dysenteriae). Conclusion: The results of this study revealed the efficacy of GLD against drug-resistant Shigella spp. and thus could be considered for the treatment of diarrhoea. GLD can be a cost-effective alternative to antibiotics.