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【Objective】 Prolonged drought followed by flooding is a phenomenon facing rice production in Southern China. This paper investigates the efficacy of fertilization and oxygenation in mitigating rice yield reduction induced by a rapid shift from drought to flooding. 【Method】 The experiment was conducted in pots, with the locally grown late rice variety Yexiangyouhang 1 573 used as the model plant. The severity of drought was mimicked by controlling the soil water content at a percentage of the field capacity, and the flooding was mimicked by keeping a water level on the soil surface; oxygenation was to dissolve oxygen into the irrigation water. Conventional irrigation and fertilization used locally was taken as the control. All treatments considered a single shift from drought to flooding, and they differed only in drought and flooding severity. A quadratic regression model was used to describe the relationship between rice yield and the four factors, with model coefficients being estimated by the quadratic saturated D-optimal design. 【Result】 ① The effect of a single factor on the rice yield was ranked in the order of: flooding > oxygenation > fertilization > drought. The two-factor effect on the rice yield was ranked in the order of: oxygenation -fertilization > drought-oxygenation > drought-flooding > drought-fertilization > flooding-oxygenation > flooding-fertilization. A light drought can improve the efficacy of oxygenation and fertilization in mitigating the yield reduction, but severe drought and flooding substantially reduced the rice yield. ② With the increase in drought and fertilization, rice yield increased first and then declined; increasing flooding severity led to a yield reduction; increasing oxygenation increased yield. ③ Optimization calculation showed, compared to the CK, oxygenation and fertilization can ameliorate the yield reduction to 39.47% on average, compared with the average yield reduction of 49.01% without fertilization and oxygenation. 【Conclusion】 The proposed model accurately describes the effect of drought, flooding, fertilization and oxygenation on rice yield, with R2=0.978, F=118.55 and P