Honey and silver have been used since ancient times for treating wounds. Their widespread clinical application has attracted attention in light of the increasing prevalence of antibiotic-resistant bacteria. While there have been a number of studies exploring the anti-inflammatory and antibacterial effects of manuka honey and nanocrystalline silver, their advantages and limitations with regard to the treatment of chronic wounds remain a subject of debate. The aim of this paper is to examine the evidence on the use of nanocrystalline silver and manuka honey for treating diabetic foot ulcers through a critical and comprehensive review of in vitro studies, animal studies, and in vivo studies. The findings from the in vitro and animal studies suggest that both agents have effective antibacterial actions. Their anti-inflammatory action and related impact on wound healing are unclear. Besides, there is no evidence to suggest that any topical agent is more effective for use in treating diabetic foot ulcer. Overall, high-quality, clinical human studies supported by findings from the molecular science on the use of manuka honey or nanocrystalline silver are lacking. There is a need for rigorously designed human clinical studies on the subject to fill this knowledge gap and guide clinical practice.