Background: Silicosis is a severe occupational disease induced by silica inhalation. It is characterized by chronic persistent pulmonary inflammation and progressive widespread interstitial lung fibrosis with worldwide prevalence. The purpose of this study was to elucidate whether fluorofenidone (AKF-PD), a newly developed anti-fibrotic chemical, can prevent pulmonary fibrosis and inflammation induced by silica. Methods: Male C57BL/6J mice were used to develop a silicosis model and randomly divided into three groups: the control group (abbreviated as Control), the silica-treated group (abbreviated as Silica), and the silica plus AKF-PD treated group (abbreviated as AKF-PD). Pathological changes in the tissue of the lungs were examined using Hematoxylin and eosin (HE) and Massons trichrome staining methods. Western blot analysis was used to assess the expression levels of α-smooth muscle actin (α-SMA), fibronectin, caspase-1, pro-caspase-1, and pro-interleukin (IL)-1β in lung tissues. Moreover, the levels of inflammatory cytokines were determined using their corresponding Enzyme-linked Immunosorbent Assay (ELISA) kits. Before the stimulation with 100 μg/mL nano-silica, the THP-1 cells were pre-treated with either AKF-PD (400 μg/mL) or serum-free RPMI-1640 medium. Additionally, we evaluated the proteins involved in the assembly of the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes in the cell and the production of inflammatory cytokines in the cell medium. Moreover, we assessed the expression levels of phosphorylated NLRP3, phosphorylated apoptosis-associated speck-like protein containing with CARD domain (ASC), and the proteins involved in the assembly of the NLRP3 inflammasomes in the lung tissues mice. Results: We observed that AKF-PD treatment significantly reduced alveolitis (p < 0.001), lung fibrosis (p < 0.01), and collagen III distribution (p < 0.0001) in the silica-induced silicosis model mice. AKF-PD decreased the expression levels of fibronectin (p < 0.05), α-smooth muscle actin (p < 0.05), interleukin-1β and transforming growth factor-β (p < 0.05), as well as the levels of interleukin-6 and tumor necrosis factor-α (p < 0.01) compared to the silica group. The AKF-PD treatment significantly reduced the silica-induced elevated levels of caspase-1 in lung tissues (p < 0.05), but did not reduce the expression of pro-caspase-1 and pro-IL-1β. However, AKF-PD treatment attenuated the expression levels of interleukin-1β, interleukin-6, tumor necrosis factor-α, and caspase-1 (p < 0.05) in silica-treated THP-1 cells, whereas did not reduce the expression of pro-IL-1β and pro-caspase-1 in these cells. Additionally, it was observed that AKF-PD treatment did not reduce the silica-induced elevated expressions of NLRP3 and ASC. However, it reduced the expression levels of phosphorylated NLRP3 (p-NLRP3) (p < 0.05), and phosphorylated ASC induced by silica (p < 0.05). Moreover, a similar trend in the data was observed in mouse lung tissue homogenates analysis. Conclusions: In summary, AKF-PD exhibits anti-inflammatory and anti-fibrotic effects in silicosis, reducing pulmonary inflammation and fibrosis while decreasing the release of IL-1β and the activation of NLRP3 inflammasome. These findings suggest AKF-PD as a potential therapy for silicosis-induced fibrosis.