Orange and coffee grounds by-products, rich in phenolic bioactive compounds, can be used in the food industry as antioxidants, colorants, flavorings and additives, mainly because they are solvents that are easy to prepare, have a lower cost, are thermally stable, biodegradable, renewable, and are considered GRAS (Generally Recognized as Safe). Deep eutectic solvents, which are sustainable and have lower melting points, are effective for extracting these compounds. This study aimed to evaluate the use of deep eutectic solvents (DES) in extracting Total Phenolic Compounds (TPC), from orange by-products and spent coffee grounds. DES formed by citric acid: mannitol (CM-DES), and lactic acid: glucose (LG-DES), were evaluated by varying the following parameters: water content (10–50%), solid–liquid ratio (1:5–1:50 w/w) and temperature (40–50 °C). DES citric acid: mannitol presented the best efficiency in the extraction of TPC under the conditions of 10% water, 80 °C, and solid–liquid ratio 1:10 (w/w) for the orange by-products (1782.92 ± 4.50 mg GAE/L) and 1:15 (w/w) for spent coffee grounds (1620.71 ± 3.72 mg GAE/L). The highest antioxidant activity was observed in the extraction with CM-DES for both by-products in the three methods evaluated: Ferric Reducing Antioxidant Power (FRAP) (1.087 ± 0.004 and 1.071 ± 0.006 mol ascorbic acid/L), DPPH radical scavenging activity (2,2-difenil-1-picrilhidrazil—DPPH) (0.233 ± 0.003 and 0.234 ± 0.001 mol Trolox equivalent/L), and radical cation scavenging activity ABTS (2,2-azino-bis (3-ethyl-benzothiazoline-6-sulfonic acid—ABTS) (0.284 ± 7.16 and 0.319 ± 0.002 mol Trolox equivalent/L). Therefore, DES with citric acid: mannitol is a promising alternative to conventional solvents to recover phenolic compounds in agro-industrial by-products, such as orange by-products and SCG.