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Methotrexate encapsulated nanocarriers (M‐CNCs) were synthesized via the ionic gelation method and using Taguchi design to optimize the formulation for; size, percent entrapment efficiency (%EE), and percent drug loading (%DL). The M‐CNCs are designed to improve therapeutic efficacy and minimize the side effect of Methotrexate. Various critical factors, such as pH, polymer to a cross‐linker ratio (v/v), and reaction time (h), are considered to investigate their influence on the selected responses during the optimization. The physicochemical properties and morphology of the optimized M‐CNCs were investigated by Dynamic light scattering, Fourier transforms infrared spectroscopy (FTIR), X‐ray diffraction, Thermogravimetric analysis, and High‐resolution transmission electron microscopy. Further, In‐vitro release, stability, pharmacokinetics, and toxicity were studied. The FTIR result revealed the cross‐linking between the drug and polymer. The nanocarrier was found to be stable with spherical morphology and crystalline nature. Optimized formulation shows, Zavg=155 nm, EE=87 %, and D=49 %. The In‐vitro drug release showed a controlled release profile of MTX up to 72 h. Pharmacokinetic evaluation of M‐CNCs in healthy Sprague Dawley rats showed an improvement in plasma drug concentration. Toxicity evaluation by the histology study revealed a healthy organ architecture and the absence of pathological lesions. Overall, the formulated M‐CNCs showed enhanced bioavailability with no toxicity.