Sericin is a globular protein known to have antioxidant potential due to presence of amino, carboxyl and hydroxyl groups in its structure. This study was designed to investigate the antiproliferative and apoptotic potential of sericin and sericin chitosan conjugated silver nanoparticles against colorectal cancer cells. To investigate the antiproliferative and apoptotic activity of sericin and sericin chitosan conjugated silver nanoparticles (SChiAgNPs), three human colorectal cancer cell lines (SW480, SW620, HCT116) were used. Sericin was isolated by the degumming process followed by the characterization by using FTIR, UV, XRD, and SEM techniques to confirm the isolation process and successful synthesis of SChiAgNPs. MTT assay was carried out to analyze the antiproliferative activities, while expression profiling of the genes i.e., GADD45A, BCL2, and TNF was assessed by qRT-PCR analysis. Sericin (S-Ext) and SChiAgNPs showed significant antiproliferative activities in SW480, SW620 and HCT 116 cells. Overall, there was 29-34 inhibition of viability for sericin S-Ext and 35-43 for SChiAgNPs in the three cell lines in comparison to untreated control. Expression profiling indicated the significant stimulation of GADD45A, BCL-2 and TNF genes expression in SW480, SW620 and HCT 116 cells. The GADD 45 A showed induction by 1.43-1.71-fold in SW480, 1.09-1.56-fold in SW620 and 1.25-4.55-fold in HCT 116 cells in response to treatment groups. The BCL2 showed the induction by 1.35-2.53, 1.38-3.1, and 2.32-3.76-fold in SW480, SW620, and HCT116 cells, respectively. TNF was induced by a factor of 3.9-6.43, 2.53-5.41, and 2.7-5.31-fold in in SW480, SW620, and HCT116 cells, respectively, after the exposure with compounds. Sericin and S-ChiAgNPs, showed significant growth inhibition and gene expression profiling modifications in the colorectal cancer cells. The findings provide evidence about sericin and its nanoparticle conjugates as potential anticancer medicine for colorectal cancer.