Human breast milk is a complex biological matrix that plays a central role in infant nutrition and development. It may also serve as a route of exposure to pharmaceutical residues following maternal drug use. Quantitative data on the transfer of non-steroidal anti-inflammatory drugs (NSAIDs) into breast milk are essential to support their safe use during lactation, however, available analytical methods remain limited. This study reports the development and validation of a rapid and sensitive hydrophilic interaction liquid chromatography–electrospray ionization mass spectrometry (HILIC–ESI/MS) method for the simultaneous quantitation of tenoxicam, meloxicam, piroxicam, and the metabolite 5′-hydroxypiroxicam in human breast milk. Sample preparation involves simple protein precipitation procedure using only 25 μL of human breast milk. Chromatographic separation is achieved within 8 min. The method was validated over the range of 20 to 2000 ng mL−1, with a limit of quantitation of 20 ng mL−1 and correlation coefficients greater than 0.998. This is the first HILIC–ESI/MS method for the simultaneous quantitation of the targeted analytes in human breast milk. The validated HILIC–ESI/MS method was subsequently applied to screen breast milk samples collected from ten lactating women donating to a hospital milk bank. Although oxicam NSAIDs were not detected in this cohort, the method is well-suited for targeted screening of human milk in clinical or surveillance settings, including milk banks and pharmacovigilance studies.