Like most of South Dakota, Manderson has a relatively dry humid continental climate (Köppen Dfa) with summers featuring very warm to hot afternoons and pleasant mornings, and generally freezing, though very variable, winters.

Winter weather, like all of the West River region is dominated by the extreme temperature conflicts between warm chinook winds that bring temperatures above 50 °F or 10 °C on an average of seventeen afternoons during the three winter months, and cold Arctic air that brings an average of 19.5 mornings below 0 °F or −17.8 °C.

Summer weather is generally very warm, although during dry spells when the upper-level anticyclone moves northward, long periods of sweltering and arid weather may occur: the hottest month was August 1983 with a daily mean of 78.6 °F or 25.9 °C and the hottest temperature on record 110 °F or 43.3 °C on July 2 of 1990.

The racial makeup of the CDP was 1.12% White, 98.72% Native American, and 0.16% from two or more races.

9.2% of all households were made up of individuals, and 1.8% had someone living alone who was 65 years of age or older.