Suppression of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6) along with nitric oxide reduction in RAW 264.7 cells by 7,8-dihydroxy-4-methylcoumarin, ethyl p-coumarate, ethyl caffeate and ethyl ferulate drove us to search structural-analogues of the aforementioned compounds through structure-based drug design. Docking studies revealed that substituted cinnamic acids and their ethyl esters (2-7c) showed higher GoldScore-fitness (GSF) and non-bonding interactions with target proteins than 7,8-dihydroxy-4-methylcoumarin (1a) and 7,8-dihydroxy-5-methylcoumarin (1b). With this background, the methylcoumarins (1a and 1b) and the cinnamic acid derivatives (2-7c) were fused in different permutations and combinations to generate sixty novel fused-cyclic coumarinolignans (FCLs) (8-13k). Docking studies on 8-13k indicated that several FCLs possess higher GSF, interesting active site interactions and distinctive π-π interactions compared to the standards (cleomiscosin A, diclofenac Na and prednisolone). Based on these findings, four novel FCLs (9d, 10d, 11d and 11e) were synthesized and tested for inhibition effect on TNF-α, IL-1β and IL-6 expressions in LPS and oxalate crystal-induced in-vitro models. Compound 10d exhibited significant effect (P < 0.0001 at 100 μM) with an IC50 value of 8.5 μM against TNF-α. Compound 11e possessed IC50 values of 13.29 μM and 17.94 μM against IL-6 and IL-1β, respectively. Study on SAR corroborated the requirement of C-4-methyl substituent in the coumarin moiety, dihydroxyl groups in the phenyl ring, and esterification of lignans for potent activity. Additionally, the reported excellent anti-inflammatory activity of cleomiscosin-A-glucoside was corroborated by from the higher GSF and better hydrophobic interactions than cleomsicosin A in the docking study. As an outcome, some novel and potentially active FCLs acting through NFκB and caspase 1 signaling pathways have been discovered as multiple cytokine inhibitors.