The aim of this study was to determine the concentration of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in marine sediments of a natural marine protected area (NMPA), Veracruz Reef System (VRS), in the Gulf of Mexico (GoM). This NMPA represents one of the first coastal sites with port activity in Mexico, which causes a range of human activities that require adequate planning so as not to impact and destroy this marine protected area; In this sense, this work represents the first effort aimed at diagnosing the presence of organochlorine contaminants in reef sediments from the mainland, both from the adjacent port area and from more distant regions with dominant agricultural activities that ultimately affect this NMPA. Content of organic matter (OM), carbonates and grain-size composition were determined to investigate their influence on compounds distribution in the sediment through multivariate analysis. The potential risk represented by organochlorines concentrations was evaluated taking as reference Sediment Quality Guidelines (SQGs). Levels of ∑PCBs, ∑DDTs, ∑HCHs and ∑Cyclodienes ranged from 11.59 to 29.79, < 0.01 to 34.11, 22.10 to 102.80, and 17.21–104.45 ng g−1 dry weight (DW), respectively. The statistical analysis revealed that the content of mud and organic matter were the parameters that might influence PCBs distribution in the sediment while OCPs could be influenced by sand and carbonate. The theoretical risk assessment estimated with the results obtained showed that concentrations of lindane, endrin, dieldrin and p,p’-DDT could have an adverse effect on the reef benthic community and continued monitoring is required. The data obtained on the organochlorine contaminants (OCs) considered in this work will contribute to support the strategies proposed by the Mexican federal government entity to continue with the conservation and surveillance of this NMPA and thereby guarantee the least impact derived mainly from port and related agricultural activities.