In this study, curcumin derivatives salicylidenecurcumin (CD1) and benzalidenecurcumin (CD2)] were prepared, and their biological activity was compared in in vitro selenite-induced cataract model. The antioxidant activity was studied using DPPH radical scavenging assay. Knoevenagel condensates of curcumin exhibited higher DPPH radical scavenging activity compared with curcumin. The anticataractogenic potential of curcumin derivatives was analyzed using lens organ culture method. The activity of antioxidant enzymes and calcium homeostasis was reversed to near normal levels following treatment in organ cultured rat lenses. These results indicated that curcumin and its derivatives—CD1 and CD2—are beneficial against selenite-induced cataract in vitro. Of these, CD1 is having higher bioactive potential compared with curcumin and CD2.