Objective: Colorectal cancer (CRC) ranked second in females and third in males among all type of cancers diagnosed. About 1.4 million cases took place with 693,900 deaths in 2012. It can occur either in colon or rectum. Thus, we aimed to develop and optimize oxaliplatin (OP) loaded solid lipid nanoparticles (SLNs). Materials and methods: SLNs containing tristearin, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), Lipoid S75, and Tween 80 was developed. Box–Behnken design was applied for optimization of SLNs and optimized formulation was selected for conjugation with folic acid (FA). Optimized formulations were evaluated for various physiochemical parameters viz., particle size (PS), zeta potential, %entrapment efficiency (EE), morphology, X-ray diffraction (XRD), and differential scanning calorimetry (DSC). Results and discussion: OP loaded uncoupled SLNs (OPSLNs) and OP loaded FA coupled SLNs (OPSLNFs) formulations revealed good EE, 49.2 ± 0.38% and 43.5 ± 0.59%, respectively and small PS, 146.2 ± 4.4 nm, and 158.8 ± 5.6 nm, respectively. XRD pattern and DSC results confirmed that OP was uniformly distributed in amorphous form within SLNs. In vitro drug release study of OPSLNs and OPSLNFs formulation revealed sustained drug release pattern of OP for up to 6 d. Anticancer activity on HT-29 cell line indicated the highest potency of OPSLNFs as compared to OPSLNs and OP solution. Conclusion: The present work illustrated the higher sensitivity of HT-29 cells to the drug entrapped in OPSLNFs as compared to OPSLNs and OP solution. Hence, this novel strategy might be a promising approach for the management of CRC.