Complement Factor H (CFH) is a crucial regulator of the alternative complement pathway, maintaining immune balance by preventing excessive activation that damages host tissues. This liver-derived glycoprotein binds to C3b and inhibits C3 convertase formation, with its N-terminal (CCP1–4) and C-terminal (CCP19–20) domains playing key roles in complement regulation and host recognition. In this in silico study, we explored the molecular architecture and interaction landscape of Factor H, identifying highly conserved motifs—particularly in CCP4, CCP8–9, and CCP12, as well as conserved lysine residues across CCP1–4. Motifs 11, 14, and 18 were mapped to the C-terminal domains (CCP18–20). Ligand interaction analysis revealed that heparin binds to CCP2 and CCP15, malondialdehyde binds to CCP3, N-glycoloyl-D-glucosamine to CCP11, and O-sialic acid to CCP11 and CCP12. Additionally, FH was shown to interact with endogenous ligands, including PTX3, fibromodulin, osteoadherin, chondroadherin, prion protein, adrenomedullin, and annexin II. These findings provide deeper insight into FH's role in complement-related disorders, such as aHUS, AMD, and dense deposit disease, supporting its potential as a therapeutic target for precision immune modulation.