Background: Safer analgesic strategies are needed to reduce the adverse effects associated with prolonged use of nonsteroidal anti-inflammatory drugs. The dry juice extract of Agave tequilana (ESPA), a chemically complex matrix with anti-inflammatory potential, may represent a promising adjuvant for modulating inflammatory pain. Objective: This study evaluated the antinociceptive activity of ESPA and its pharmacological interaction with diclofenac in the formalin test. Methods: BALB/c mice received ESPA or diclofenac orally 30 min before pain induction, and nociceptive behavior was quantified by counting paw flinches during the neurogenic and inflammatory phases. The GC–MS-detectable fraction of ESPA was chemically characterized, while the pharmacokinetic and bioactivity profiles of selected compounds were explored in silico using SwissADME and PASSonline. Molecular docking with COX-1 and COX-2 was performed using AutoDock Vina. Acute toxicity was evaluated according to OECD Guideline 423, and the ESPA–diclofenac interaction was examined using isobolographic analysis. Results: ESPA produced significant antinociceptive effects during the inflammatory phase. Although diclofenac exhibited greater potency, ESPA showed consistent efficacy in reducing inflammatory nociceptive behavior. GC–MS analysis identified several compounds within the detectable volatile/lipophilic fraction, including n-hexadecanoic, octadecanoic, and oleic acids. In silico evaluations suggested favorable predicted oral absorption and potential bioactivities related to inflammatory mediator regulation. Docking studies showed moderate predicted affinities for COX-1 and COX-2, lower than those observed for diclofenac. Isobolographic analysis demonstrated a synergistic interaction between ESPA and diclofenac, allowing dose reduction while maintaining antinociceptive efficacy. Acute toxicity testing indicated no signs of toxicity at the evaluated dose. Conclusions: These findings suggest that ESPA may act as a potential adjuvant in diclofenac-based analgesic strategies for inflammatory pain; however, further studies are required to clarify the active constituents and underlying mechanisms.