Watermelon (Citrullus lanatus) flesh and seeds were dried and pulverized, and their extracts were diffused to sterile discs for the evaluation of anti-microbial activity. The disc-diffusion technique was used to assess anti-bacterial activity against Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Pasteurella multocida, Yersinia enterocolitica, Serratia marcescens, Klebsiella pneumoniae, Xanthomonas campestris, Staphylococcus aureus. Anti-fungal activity against the yeasts Candida albicans and Rhodotorula glutinis was also examined. Standard anti-biotics were also tested as controls. Watermelon flesh and seed extracts were found to be effective against gram-positive and gram-negative bacteria and yeasts. The extracts were also screened for anti-oxidant activity using the 2,2-diphenyl-1-picryl-hydrazyl (DPPH) free-radical-scavenging assay, total reducing ability using the Fe3+–Fe2+ transformation method and ferrous ion (Fe2+)-chelating activity. Butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediaminetetraacetic acid and α-tocopherol were used as reference anti-oxidant radical scavenger compounds. The most potent anti-bacterial activity was demonstrated by watermelon–ethanol extract (inhibition zone 30 mm) against K. pneumoniae, and the most potent anti-fungal activity was demonstrated by watermelon–acetone extract (inhibition zone 26 mm) against R. glutinis. Watermelon–ethanol and watermelon seed–ethanol extracts both demonstrated marked anti-oxidant activity. These results highlight that watermelon fruit and seed extracts have potential for the development of efficient, safe and cost-effective natural anti-oxidant compounds for application in the functional food industries.