This study examines whether maternal low ω6:ω3 ratio diet and offspring seaweed (SW) supplementation can improve offspring immunity and performance by elucidating the effects on piglet serum proteome. A total of 16 sows were given either a standard (CR, 13:1) or low ω6:ω3 ratio diet (LR, 4:1) during pregnancy and lactation and their male weaned piglets were supplemented with SW powder (4 g/kg, SW) or not (CT) in a 21-day post-weaning (PW) diet. Four PW piglet groups were then identified based on dam and piglet treatment, namely CRCT, CRSW, LRCT, and LRSW (n = 10 each). Piglet serum collected at weaning and d21 PW were analyzed (n = 5 each) using TMT-based quantitative proteomics and validated by appropriate assays.