Elevated temperature and frequent drought events under global climate change may seriously affect soil respiration. However, the underlying mechanism of the effects of warming and drought on soil respiration is not fully understood in the context of the Loess Plateau. This study examined the response of soil respiration (Rs) to multiple factors, including warming (W), drought (P), and their interaction (WP), in the semi-arid grassland of the Loess Plateau in Northwest China. The research period was from May to November 2022, with an open-top heating box used for warming and a rain shelter used for drought. The results showed the following: (1) Rs ranged from 1.67 μmol m−2 s−1 to 4.77 μmol m−2 s−1, with an average of 3.36 ± 0.07 μmol m−2 s−1. The cumulative soil carbon flux ranged from 500.97 g C·m−2 to 566.97 g C·m−2, and the average cumulative soil respiration was 535.28 ± 35.44 g C·m−2. (2) Warming increased Rs by 5.04 ± 3.11%, but drought inhibited Rs by 3.40 ± 3.14%, and the interaction between warming and drought significantly reduced soil respiration by 11.27 ± 3.89%. (3) The content of particulate organic carbon (POC), dissolved organic carbon (DOC), soil organic carbon (SOC), and readily oxidized carbon (ROC) decreased with the increased soil depth. ROC after W and WP treatments was significantly higher than that of the control, and POC after P treatment was significantly higher than CK (p < 0.05). (4) The seasonal variation of soil respiration was positively correlated with soil temperature, soil water content, plant height, and leaf area index (p < 0.05), but the response rules differed during different regeneration periods. Soil water content; soil water content and leaf area index; and soil water content, soil temperature, and leaf area index were the factors that regulated the variation in soil respiration in the first, second, and third regeneration periods, respectively. These results clearly showed the limiting effect of drought stress on the coupling between temperature and soil respiration, especially in semi-arid regions. Collectively, the variations in soil respiration under warming, drought, and their interactions were further regulated by different biotic and abiotic factors. Considering future warming, when coupled with increased drought, our findings indicate the importance of considering the interactive effects of climate change on soil respiration and its components in arid and semi-arid regions over the next decade.