Aims: To investigate the effect of natural products on the spore cycle of Clostridium difficile in vitro. Methods and Results: Twenty-two natural products were investigated using four C. difficile strains. Effects on sporulation, determined using microscopy and a conventional spore recovery assay, showed that fresh onion bulb extract (6·3% v v−1) and coconut oil (8% v v−1) inhibited sporulation in all four isolates by 66–86% and 51–88%, respectively, compared to untreated controls. Fresh ginger rhizome extract (25% v v−1) was also inhibitory, although to a lesser extent. Using a standard spore germination and outgrowth assay, germination was unaffected by the 22 products, whereas outgrowth was significantly reduced by artichoke extract (18·8 mg ml−1), fresh onion bulb extract (25% v v−1), Leptospermum honeys (8% w v−1) and allicin (75 mg ml−1; P < 0·01). Sporicidal activity, investigated using a standard plate recovery assay, was minimal. Conclusions: Three of the 22 natural products (13%) showed inhibitory effects on sporulation of C. difficile and six products (27%) reduced vegetative outgrowth of C. difficile. Significance and Impact of the Study: This study shows the potential of natural products to inhibit different stages of C. difficile sporulation and encourages further investigation in this field.