In this study, we have investigated new lipid-drug conjugates (LDCs) of methylprednisolone. Methylprednisolone is a corticosteroid medication, for the potential treatment of inflammatory diseases. The LDCs 1-2; methylprednisolone palmitate (1) and methylprednisolone palmityl carbonate (2), were designed by conjugating a C16 aliphatic chain via an ester or carbonate bond, respectively. Their structures were comprehensively characterized using mass spectrometry, nuclear magnetic resonance spectroscopy, and infrared spectroscopy. These LDCs 1-2 were subsequently formulated into nanoscale particles (NPs) using ethanol injection method. Hydrogenated soybean phosphatidylcholine (HSPC) and tween-80 served as excipients in the NPs formulation. Characterization via dynamic light scattering, scanning electron microscopy, and atomic force microscopy confirmed the formation of spherical NPs with a diameter ranging from 100 to 120 nm. The LDCs NPs 1-2 exhibited excellent stability for about a month, with good polydispersity (below 0.2) and a negative zeta potential between -20 mV to -34 mV. Encapsulation efficiency of the LDCs within the LDCs NPs 1-2 surpassed 90%, as determined by HPLC analysis. In vitro cytotoxicity studies utilizing LPS-activated THP-1 cells demonstrated no adverse effects associated with LDCs NPs 1-2 at concentrations up to 100 μg/mL. Furthermore, the LDCs NPs 1-2 effectively retained the anti-inflammatory activity, as evidenced by the suppression of IL-1β, TNF-α, and MCP-1 secretion in LPS-stimulated THP-1 cells. The therapeutic potential of these LDCs NPs 1-2 was further evaluated in rat intervertebral disc-derived nucleus pulposus cells (NPCs). Curative and preventive treatment regimens with the free drug and LDCs NPs 1-2 were employed. Quantitative PCR analysis revealed a significant downregulation of pain and inflammation markers (Substance P and COX-2) along with a concomitant upregulation of antioxidant markers (GPX1, PRDX1, and SOD1) in NPCs treated with both the drug and LDCs NPs 1-2 compared to oxidative stress-induced and control NPCs. Our novel LDCs NPs 1-2 exhibited promising therapeutic potential for treating inflammatory and pain related complications, (including intervertebral disc degeneration). This promise stems from their multifaceted properties, encompassing anti-inflammatory, antioxidant, and analgesic effects. Further research is warranted to fully explore LDCs NPs 1-2 as potential drug candidates in future pre-clinical and clinical trials.