In the last decade, massive events of Sargassum influx have been reported causing ecological and economic damages. In this study, we evaluated the antioxidant potential of the holopelagic species S. fluitans, S. natans I, and S. natans VIII that arrived during 2018–2019 on the Mexican Caribbean coast. The seasonality and intra-thallus variation (axes, leaves, and vesicles) of the total phenolic content (TPC) and antioxidant activity were determined in algal crude extracts. The antioxidant potential was assessed using a 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging assay, a 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) free radical scavenging assay and a ferric reducing antioxidant power (FRAP) assay. All Sargassum species showed radical scavenging and reducing power due to their polyphenol content, but also due to the presence of other antioxidant metabolites such as mannitol, alginate, and fucoidan as observed in the 13C-NMR spectra. In the summer months, coinciding with elevated seawater temperatures and the highest solar irradiances, the antioxidant capacity and the TPC in all Sargassum species were enhanced. For all the holopelagic species of Sargassum studied, the highest TPC was obtained in the axes rather than in the vesicles or leaves. The results suggest that invasive Sargassum biomass in the Mexican Caribbean contains different compounds with antioxidant properties and could be considered, especially in the summer months, as a natural alternative to synthetic antioxidants.