Here we describe an ultra-sensitive reverse phase liquid chromatographic method for the simultaneous determination of carbamazepine with NSAIDs in API, pharmaceutical formulation and human serum with UV detection. The separation of these multiple drug components was made by a Bondapak C 18 column (10 µm, 25 cm×0.46 cm) using a moderate acidic mixture of mobile phase i.e., methanol:water 80:20 with pH adjusted to 3.0 using 85% o-phosphoric acid. The flow rate of the mobile phase was affixed at 1.0 ml min -1 for the best minimum interval of elusion of all the analytes. The detector response was monitored at isobestic point of 220 nm at ambient temperature. Calibration curves were obtained in the range of 0.4-12 µg mL -1 for carbamazepine, 0.5-16 µg mL -1 for meloxicam and 0.25-8.0 µg mL -1 for ibuprofen and mefenamic acid. Limits of detection were found to be 4.0, 3.0, 1.0, and 13.0 ng mL -1 respectively. The method was compared by programming the detector at individual wavelength of components which showed more sensitivity with linear range 0.10-3.0, 0.15-5.0, 0.10-3.0 and 0.125-4.0 µg mL -1 and detection limits 2.0, 2.0, 1.0, and 3.0 ng mL -1 respectively. ICH guidelines were followed for validation study. The method showed good precision and accuracy within acceptable range and can be successfully applied for the determination of these drugs in pharmaceutical formulations, human serum and clinical laboratories without interference of excipients or endogenous components of serum. In vitro interaction studies have also been carried out at physiological temperature in buffers of various pH (4, 7.4 and 9.0) simulating human stomach environments and % availability has been calculated. Moreover, the solid charge transfer complexes of carbamazepine with interacting NSAIDs were synthesized and characterized by IR spectroscopy and verified by computational molecular modeling.