The concept of slippery lubricant-infused surfaces has shown promising potential in anti-fouling for controlling detrimental biofilm growth. In this study, non-toxic silicone oil was either impregnated into porous surface nanostructures, referred as liquid infused surface (LIS), or diffused into a polydimethylsiloxane (PDMS) matrix, referred to as a swollen PDMS (S-PDMS), making two kinds of slippery surfaces. The slippery lubricant layers have extremely low contact angle hysteresis and both slippery surfaces showed superior anti-wetting performances with droplets bouncing off or rolling transiently after impacting the surfaces. We further demonstrated that water droplets can remove dust from the slippery surfaces thus showing a “cleaning effect”. Moreover, “coffee-ring” effects were inhibited on these slippery surfaces after droplet evaporation, and deposits could be easily removed. The clinically biofilm-forming species P. aeruginosa (as a model system) was used to further evaluate the antifouling potential of the slippery surfaces. The dried biofilm stains could still be easily removed from the slippery surfaces. Additionally, both slippery surfaces prevented around 90% of bacterial biofilm growth after 6 days, compared to the unmodified control PDMS surfaces. This investigation also extended across another clinical pathogen, S. epidermidis, and showed similar results. The anti-wetting and anti-fouling analysis in this study will facilitate the development of more efficient slippery platforms for controlling biofouling.