Current analgesics on the market exhibit a short duration of action and induce the production of inflammatory factors in tissues damaged by surgical procedures. Inflammatory factor production can create acidic environments, limiting drug delivery. In this study, we developed a novel injectable formulation comprising bupivacaine multivesicular liposomes of high osmotic pressure (H-MVL) and meloxicam nanocrystals (MLX) in a thermosensitive gel (H-MVL/MLX@GEL) adapted to the microenvironment for long-term postoperative analgesia. To achieve formulation stability, H-MVL were prepared by regulating the osmotic pressure of the gel system. Moreover, the inclusion of MLX serves to not only attenuate local inflammatory factors, regulating the acidic microenvironment, but also to prolong the duration of action of meloxicam (MEL). The increased absorption of bupivacaine (BUP) and the prolongation of the half-life of BUP release in H-MVL/MLX@GEL were demonstrated through pharmacokinetic experiments. Sciatic nerve block models and hot plate analgesia tests demonstrated that H-MVL/MLX@GEL effectively alleviated pain for at least five days. The immunohistochemical results showed that the addition of MLX reduced the production of the local inflammatory factors interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), thereby improving the analgesic effect by regulating the local acidic environment and alleviating local irritation.