This study highlights the level of microbial contamination of waterpipe components in selected area of Saudi Arabia and the resistance of selected bacteria to different antibiotics was determined. A series of biochemical tests, microscopic examination, and screening on Vitek 2 compact (bioMérieux Inc., USA) system were done to characterize the bacterial isolates. Out of 132 samples investigated, 7 mouthpiece samples and 48 water bowl samples showed positivity on culture. The percentage of contamination rate was higher in water bowl (69.69%) than in mouthpieces (10.6%) for all selected areas. A total of 55 bacterial isolates were identified which included Gram-negative (28) and Gram-positive (27) bacteria. Antimicrobial susceptibility data showed more resistance to bacteria isolated from water bowl than bacteria isolated from mouthpiece. In addition, one isolate which was confirmed as methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae was resistant to antibiotics which are commonly used to treat pneumonia. Water bowl of waterpipe instrument is significantly contaminated with different bacterial pathogens including multidrug-resistant and pneumonia causing bacteria, which are a real health concern among waterpipe smokers. The presented data could assist public health professionals to raise the concerns regarding cleaning practices of waterpipe components and highlights the risk posed among the waterpipe smokers.