Objective To investigate whether modulation of the host lung tissue PPAR-γ/RXR-α signaling attenuates inflammation induced by Paragonimus proliferus (P. proliferus) infection by elevating the rate of fatty acid β-oxidation, thereby providing a scientific basis for the prevention and control of P. proliferus. Methods A rat model of pulmonary paragonimiasis induced by P. proliferus infection was established and treated with either the PPAR-γ agonist rosiglitazone or the RXR-α agonist bexarotene for intervention. Then, whole-transcriptome sequencing of rat lung tissues was performed on the DNBSEQ platform. qRT-PCR, western blotting, and immunofluorescence were used to quantify the mRNA and protein expression of key target molecules of PPAR-γ/RXR-α signaling, respectively. Co-immunoprecipitation (CoIP) was used to assess the protein-protein interactions between PPAR-γ and RXR-α. The rate of fatty-acid β-oxidation in lung tissue was measured colorimetrically, and serum levels of IL-1β, IL-6, and TNF-α were determined by ELISA. Results Transcriptome analysis revealed differential expression of fatty-acid β-oxidation-related genes, including Cpt1a, Cpt1b, Cpt1, Cpt1c, Cpt2, Fabp4, Fabp5, Fat4, Acox1, Rxr-α, and Rxr-b in the rat model of P. proliferus infection. qRT-PCR, western blotting, and CoIP assays showed that the mRNA and protein expression of PPAR-γ and RXR-α were down-regulated in rat lung tissues of the model group, whereas both bexarotene and rosiglitazone significantly restored their expression and enhanced PPAR-γ/RXR-α interaction (all P<0.05). The fatty acid β-oxidation rates of the rat lung tissues in healthy control, model, bexarotene, and rosiglitazone groups were 60 (55.76, 64.92), 44 (41.33, 47.77), 63.00 (54.00, 67.41), and 59.90 (49.60, 67.00) μmol/(min·mg), respectively. Corresponding serum IL-1 levels were 105.61 (96.52, 113.90 ), 147.54 (143.32, 182.88), 94.98 (92.85, 111.25), and 94.25 (79.61, 115.22) pmol/L; IL-6 levels were 1 398.06 (1 258.22, 2 220.21), 4 538.12 (3 427.64, 5232.93), 1 950.00 (1 429.68, 2 359.00) and 663.91 (604.67, 770.61) pg/mL; and TNF-α levels were 153.86 (136.50, 156.88), 183.1847 (169.58, 194.24), 151.78 (144.69, 162.48) and 165.90 (158.97, 171.78) pmol/L, respectively. Overall differences among the four groups were significant (H=10.45, 13.24, 19.72, and 13.59, all P<0.05); furthermore, the model group differed from the healthy control, and both treatment groups (bexarotene or rosiglitazone group) differed from the model group (all P<0.05). Conclusion Activation of PPAR-γ/RXR-α signaling reduces the level of inflammation induced by P. proliferus infection by elevating the rate of fatty acid β-oxidation in rat lung tissues.