Endoluminal surgery for the treatment of colorectal neoplasia is typically carried out using electrocautery tools which imply limited precision and the risk of harm through collateral thermal damage to the adjacent healthy tissue. As a potential alternative, we present the successful colonic epithelial laser ablation by means of picosecond laser pulses. Laser ablation studies performed in ex-vivo colon tissue result in cavities with comparable thickness to early stage colorectal cancers. The corresponding histology sections exhibit only minimal collateral damage to the surrounding tissue and the depth of the ablation can be controlled precisely by means of the pulse energy. High-speed imaging has been used for the first time to visualize picosecond laser ablation of cancerous tissue in a clinically relevant model. This information was correlated with histopathology and optical surface profilometry revealing the dynamic nature of the laser tissue interaction and the need for temporal or spatial separation of pulses for optimum efficacy with regards to tissue removal. Overall, the application of picosecond laser pulses to ablate endoluminal bowel lesions demonstrates significantly improved precision and reduced thermal damage to the adjacent tissue in comparison to conventional procedures and hence will enable more precise surgical treatment of cancers.