The objective of this research was to develop a bio-based paper strengthening agent for the replacement of petroleum-based paper wet strengthening agents like polyamide epichlorohydrin (PAE) and glyoxylate polyacrylamide (GPAM), especially for the application of hygienic paper products. Cornstarch was modified with 2-chloroacetamide in the presence of sodium hydroxide in aqueous media through etherification. The modification reaction conditions, such as modifying agent concentration, solid-to-liquor ratio, reaction time, and temperature, were optimized based on an acetamide functional group incorporated into cornstarch. Further, modified cornstarch was reacted with glyoxal to produce glyoxylate starch-amide. Two percent glyoxylate starch-amide (based on dry pulp) was thoroughly mixed with recycled old corrugated containerboard (OCC) pulp slurry before preparing the paper to test the physical properties. The wet tensile index, dry tensile index, and dry burst index of the glyoxylate starch-amide-treated OCC paper increased by 429, 39, and 44%, respectively, compared to the control sample. In addition, comparative studies were done between glyoxylate starch-amide and commercial paper strengthening agents GPAM and PAE. The wet tensile index of 1% glyoxylate starch-amide-treated tissue paper was about 60–70% higher than commercial GPAM and PAE. The increase in wet strength of paper products was in agreement with increased covalent bonding between glyoxylate starch-amide and pulp fiber.