To investigate the etiological cause of rheumatoid arthritis (RA) and reveal the mechanism underlying the artemisinin and rapamycin against RA, the present work has established a mouse model of the complete Freund’s adjuvant (CFA)-induced acute arthritis (CIAA). The inflammation morphological and histopathological comparisons of CIAA with the classic collagen-induced arthritis (CIA) indicated that CIAA perfectly simulates CIA in articular erythema and edema, synovial hyperplasia, and inflammatory infiltration in a substantially shortened modeling time (from 28 to 3 d). Intra-articular injection with CFA allows global up-regulation of pro-inflammatory cytokine genes, dramatic burst of nitric oxide (NO), overexpression of hypoxia inducible factor 1 alpha (HIF-1α) and vascular epithelial growth factor (VEGF), and synovial angiogenesis and hyperplasia. Articular injection of mice with the NO donor compound sodium nitroprusside (SNP) also causes articular erythema and edema, whereas co-administration of CFA with the NO synthetic inhibitor NG-monomethyl-L-arginine (L-NMMA) abrogates articular inflammation. SNP activates pro-inflammatory cytokines but suppresses inducible NO synthase within three days, and upregulates HIF-1α and VEGF within two weeks. Pre- and post-injection of modeling CIAA mice with artesunate and/or rapamycin reverses hypoxia-induced expression of HIF-1α and VEGF, synovial angiogenesis, tumor-like hyperplasia, and lymphocytic inflammatory infiltration. While artesunate fails to completely repress CFA-induced immune activation, rapamycin down-regulates CFA-triggered expression of pro-inflammatory cytokines. Nevertheless, both artesunate and rapamycin are able to inhibit NO production. Conclusively, NO serves as a pivotal mediator of RA pathogenesis, and artemisinin and rapamycin, by blocking NO generation, hold potential promise in prophylactic and therapeutic interventions of RA patients.