Background: Streptococcus mutans and Candida albicans are the chief microbes associated with severe early childhood caries (S-ECC). Diverse antimicrobial agents are widely used to prevent ECC, and a quest for newer natural products has been on the rise in the recent past. Aim: To estimate the antimicrobial activity of propolis with chlorhexidine on salivary specimens from children with S-ECC in vitro. Materials and methods: A total of 60 children with S-ECC were designated. Salivary samples of 30 children (group I) were inoculated onto mitis salivarius agar (MSA) to isolate S. mutans. Another 30 samples (group II) were inoculated on sabouraud's dextrose agar and subcultured on HiCrome Candida differential agar to isolate C. albicans. Sensitivity testing for 0.2% chlorhexidine and 10% propolis extract was done using the agar well diffusion technique using Mueller–Hinton agar medium. The antimicrobial effect was evaluated by calculating the diameter of the zone of inhibition surrounding the well. Results: All saliva samples collected from groups I and II showed growth of S. mutans and C. albicans, respectively. All cultured microbes were sensitive to 0.2% chlorhexidine and 10% propolis extract. The mean inhibition zone for S. mutans with chlorhexidine was 14.57 ± 0.63 mm, and with propolis, 11.93 ± 0.52 mm. The mean zone of inhibition for C. albicans with chlorhexidine was 12.83 ± 0.59 mm, and with propolis, 9.50 ± 0.73 mm. Chlorhexidine consistently showed statistically significantly larger zones of inhibition and hence appeared to be a more potent antimicrobial agent than propolis extract for both S. mutans and C. albicans. However, propolis has irrefutable action against both S. mutans and C. albicans. Conclusion: Propolis may be an acceptable substitute for chlorhexidine for long-term use as it has demonstrated antimicrobial activity and fewer side effects. Hence, this Association of Physicians of India herbal drug can be incorporated into mouthwashes and toothpaste to reduce microbial counts.