Both the economic loss and welfare implications of lameness vastly impact the dairy industry. There is a need for effective modalities of analgesia to minimize welfare concerns regarding lameness associated pain in lactating dairy cattle. To date, there are no labeled products with pain control indications available for lactating dairy cattle in the United States. Non-steroidal anti-inflammatory drugs (NSAIDs), like meloxicam and flunixin meglumine, are commonly used by veterinarians for pain management. Data is limited as to their efficacy in lameness-associated pain management. The overarching goal of this study was to compare the analgesic effects of flunixin meglumine (IV) and meloxicam (PO) in lactating dairy cattle with experimentally induced lameness via intra-articular injection of amphotericin B. We hypothesized that lameness would improve under meloxicam treatment compared to flunixin meglumine or no treatment control. A double blinded, randomized controlled trial involving positive and negative controls created the framework to assess efficacy parameters. Parameters included pressure algometry, pressure mat analysis, lameness score, infrared thermography imaging, substance P, and cortisol concentrations of 48 lactating Holstein cows across a six-day time period. Intra-articular injection with amphotericin B resulted in mild transient lameness. Results indicated statistically significant treatment by time effects for several parameters. Visual lameness scores showed flunixin meglumine was equally effective to meloxicam and both more effective than the positive control (P < 0.0001). Flunixin meglumine administered animals displayed lower cortisol levels to that of meloxicam treated cows and both more effective than the positive control (P = 0.0008). The cows treated with meloxicam withstood a greater force created by mechanical nociception threshold than cows administered flunixin meglumine and both more effective than the positive control (P = 0.0008). The impact of NSAID use as a therapeutic treatment of lameness is insurmountable in combatting welfare concerns in the dairy industry.