Triple negative breast cancer (TNBC) is a subtype of breast cancers that lacks effective targeted therapy and has poor clinical outcomes. Hence, new strategies are needed for treating TNBC. Marine sponges have historically been a source of anticancer compounds and sponges from the Western Australian coast have so far received little attention. Thus, this study focused on screening WA marine sponges for cytotoxic activity in TNBC. Bioassay-guided fractionation of two active sponges Monanchoraviridis and Manihinea lynbeazleyae resulted in isolation of crambescidin 800 and aurantoside C as active compounds, which were also investigated for their mechanism of action in TNBC.