Driven by anthropogenic activities, freshwater salinization has become an emerging global environmental issue. Recent studies indicate that salinization increases the mobility of heavy metals in soil and causes higher flux into surface waterbodies. The present study assessed the combined effects of salinization (0, 3, 6 PSU) and the heavy metal Cd2+ (0, 0.2, 0.4 mg L−1) on the anti-grazing colony formation and population growth of Scenedesmus obliquus, a common freshwater alga. The results showed that the increase in salinity promoted colony formation of S. obliquus with or without the presence of grazing cues and, in contrast, Cd2+ contamination depressed the defensive colony formation of S. obliquus to Daphnia filtrate. The increase in both salinity and Cd2+ concentration depressed the population growth of S. obliquus, including impaired photosynthesis and a decreased population growth rate. Salinization moderated the negative effects of Cd2+ on defensive colony formation of S. obliquus, suggesting increased absorption of Cd2+ ions by a thicker outer layer of the algal cell wall under saltier conditions. As a result, larger defensive colonies of S. obliquus under freshwater salinization may cause higher bioaccumulation of heavy metals by algal cells and heavier influence on zooplankton. This study provides evidence that freshwater salinization could interfere with plankton interactions by affecting algal defense and growth, which may lead to bottom-up cascading effects on freshwater food webs.