Angiogenesis refers to the generation of new blood vasculature from the nearby pre-existing one and is regulated by a balance between the pro- and anti-angiogenic factors. During carcinogenesis, pro-angiogenic factors dominate and initialize the growth of new blood capillaries to provide nutrition, growth factors and overcome hypoxia inside the tumor microenvironment. In the present study, we have observed the role of Phosphatidylinositol-3-kinase (PI3-K)/Phophatase and tensin homolog deleted on chromosome ten (PTEN)/Akt (Protein kinase B) pathway and canonical Wnt/β-catenin downstream signaling in the regulation of various pro-angiogenic molecules including the vascular endocrine growth factor-A (VEGF-A), matix metalloproteinases (MMPs), inducible nitric oxide synthase (iNOS) and chemokines for the progression of experimental colorectal cancer with 1,2-dimethylhydrazine dihydrochloride (DMH) and anti-angiogenic effects of two non-steroidal anti-inflammatory drugs (NSAIDs) viz. Sulindac and Celecoxib. Morphological and histopathological studies were performed to analyze the tumorigenic modifications while flow cytometry for the relative quantification of apoptotic events. Transcriptional and translational modifications of biomolecules were analyzed via Reverse Transcriptase-and quantitative Real Time PCR, Western immoblotting and immunoflurescence, respectively. In vitro phosphorylation, gelatin zymography and nitric oxide (NO) assay were performed to observe the activation states of Akt, MMPs and iNOS enzyme, respectively. Dysregultion in Akt activation, and thereby, aberrant signaling of β-catenin along with the production of NO could positively regulate tumor angiogenesis. NSAIDs can overcome these carcinogenic effects by controlling various key check points including higher PTEN and glycogen synthase kinase-3β (GSK-3β) expression and repressing Akt, MMPs and iNOS activation while inducing apoptosis among the cancer cells.