Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation, pain, stiffness, and swelling in the affected joints typically with a symmetrical pattern on both sides of the body, which becomes more drastic and can also affect other organs and systems in the body. Thus, regular monitoring, follow-up of the disease, and exploring new metal-based therapy with minimum or no side effects are important challenges for managing the disease effectively. Methods: Complexes with the common formula [M(L)(OAc)] (M = Cu (II) or Zn (II)) and HL = 2-(-3-hydroxy-2-naphthoyl)-3,4,4a,5,10,10a-hexahydro-1H-5,10-benzeno-benzo [g] phthalazine-1,4-dione) were synthesized through a reaction between phthalazinedione derivative (HL) and Cu (II) and Zn (II) acetates. For synthesis and description of the HL, various elemental analyses, UV-Vis, infera red (IR), 1H-NMR, 13C-NMR, conductance, thermal gravimetric analysis (TGA), and magnetic moments were accurately performed. Additionally, the analgesic and anti-inflammatory activities of phthaline metal compounds were identified using adjuvant arthritis model comprising of forty-eight Sprague-Dawley rats (200–250 g). In that model, the rats were categorized into two main groups: control group (received sodium carboxymethyl cellulose (SCMC) solvent, n = 6) and arthertis group (n = 42). In arthertic group, the rats had been inoculated by the reagent of collagen-adjuvant arthritis into the left paw pad. After 45 days, the arthertic rats were further divided into seven different groups (n = 6 each): arthritic control, piroxicam-treated, zinc acetate-treated, copper acetate-treated, HL, copper complex-, and zinc complex-treated groups. Then for all treated and non-treated rats, paw edema, pain and pressure tolerance measurements, and mobilization tolerance (pain scoring) were identified as measures of improvement in the disease activity following the respective piroxicam as standard and metal compounds. Results: Phthalazine Copper (II) and Zinc (II) complexes showed anti-inflammatory action against rheumatoid arthritis as predicted by an equation with a regression correlation (R² = 0.95) calculated using quantitative structure activity relationship (QSAR) analysis. The anti-inflammatory activity of synthesized phthalazine metal complexes was supported by the application of docking analysis and in vivo model of collagen adjuvant arthritis in rats, respectively. The results of docking showed that phthalate-zinedine derivatives in keto form structure have a MolDock Score of –130.726 Kcal/mol and a MolDock Rerank Score of –96.2 Kcal/mol, respectively. These suggest that phthalazinedione derivatives in keto form are strong and anchored with a cyclooxygenase-2 active site, which consequently decreases the inflammatory pathways associated with the progression of rheumatoid arthritis (RH). RH rats treated with piroxicam reported significant (p = 0.001) anti-inflammatory activity with an improved bor RI and analgic effects measured by both increase in pain tolerance and decrease in pain score compared to RH- non-treated rats. In addition to that, significant (p = 0.01) analgesic and anti-inflammatory effects of the ligand (HL) and its copper and zinc complexes than piroxicam RH treated rats and non-treated RH rats, respectively, were reported when the complexes were applied to in vivo rat models with collagen adjuvant arthritis. Conclusions: Phthalazinedione derivative (HL), Cu (II), and Zn (II) acetates combined to treat rheumatoid arthritis (RH) show a good docking with inflammatory enzyme cyclooxygenase-2 (COX-2), with improved anti-inflammatory activities against RH as measured by docking and in vivo rat model of collagen adjuvant arthritis. In addition, the newly synthesized phthalazine metal complexes disclosed a significant anti-inflammatory and analgesic effect sequenced as [Zn(L)(OAc)] > HL > [Cu(L)(OAc)].