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Aim & Objective: This study evaluates the potential of combining paclitaxel (PTX) and bortezomib (BTZ) for breast cancer therapy. Materials & Methods: The nanoformulation was optimized via Box-Behnken Design (BBD), with method validation adhering to US-FDA guidelines. Results: Multiple reaction monitoring transitions for PTX, BTZ and internal standard were m/z 855.80→286.60, 366.80→226.00 and 179.80→110.00, respectively. Elution done on C18 Luna column with 0.1% FA in MeOH:10 mM ammonium acetate. The size of nanoformulation was 133.9 ± 1.97 nm, PDI 0.19 ± 0.01 and zeta potential -19.20 ± 1.36 mV. Pharmacokinetics showed higher Cmax for PTX-BTZ-NE (313.75 ± 10.71 ng/ml PTX, 11.92 ± 0.53 ng/ml BTZ) versus free PTX-BTZ (104 ± 13.06 ng/ml PTX, 1.9 ± 0.08 ng/ml BTZ). Conclusion: Future findings will contribute to the treatment of breast cancer using PTX and BTZ. Graphical Abstract Article highlights The importance of paclitaxel (PTX) and bortezomib (BTZ) in combination with chemotherapy is demonstrated by recently published studies. An obstacle to measuring the results of translational research is the lack of an analytical or bioanalytical approach for simultaneously estimating PTX and BTZ. A gap in the scientific literature has been filled by the development and validation of an LC-MS/MS method for the co-estimation or simultaneous measurement of PTX and BTZ. Both moieties were resolved in a Phenomenex Luna (C18), (7.5 × 4.6 mm, 3μ) column with a 0.1% FA in MeOH:10 mM ammonium acetate, 80:20 (% v/v) mobile phase at 0.6 ml/min flow rate. According to the US-FDA, the developed method was validated in female Sprague–Dawley rats plasma for different characteristics, such as linearity, precision and accuracy, LLOQ and stability studies. The oral P.K profile of PTX and BTZ co-loaded in a nanoformulation has been investigated in young female Sprague–Dawley rats to support the applicability of the established LC-MS/MS methodology. With an LLOQ of 1.0 ng/ml for each drug and a run time of 6.0 min, the calibration curve was found linear for the 1–600 ng/ml concentration range. The proposed LC-MS/MS method was confirmed to be repeatable, precise and accurate. The developed LC-MS/MS method was successfully illustrated for the co-estimation or simultaneous estimation of both drugs in rat plasma to generate an oral P.K profile. US-FDA Guidance of Industry and Bioanalytical Method Validation criteria was followed for the co-estimation of PTX and BTZ and was applied to nanoformulation development and bioanalytical investigations. [ABSTRACT FROM AUTHOR]