Purpose: To evaluate the evolution of perceived quality of life in relation to oral health during pregnancy and to determine the risk factors involved in this process. Methods: A follow-up study was carried out with pregnant Spanish women. Two oral examinations and an oral health-related quality of life (OHRQoL) assessment, using the OHIP-14 questionnaire, were performed in the first and third trimester of pregnancy. Data on sociodemographic characteristics, medical history, O’Sullivan Test measures, oral hygiene habits, history of caries, and periodontal status of participants were collected through structured medical-dental questionnaires. Results: A complete dataset comprising 246 pregnant women was available for analysis. Overall scores for negative impacts on the OHIP questionnaire were significantly higher during late pregnancy (74%). This indicated a deterioration in oral health-related quality of life amongst participants. Items describing “painful aching”, “self-consciousness”, “unsatisfactory diet”, and “interrupted meals” showed the greatest increase between the first and third trimester of gestation. Multivariate analysis showed that pre-gestational/gestational diabetes mellitus and poor oral hygiene habits during the first trimester of gestation were directly associated with worse oral health-related quality of life during the third trimester of gestation (hyperglycemia: OR 2.86; 95% CI 1.019–8.050: p = 0.043 / oral hygiene: OR 1.33; 95% CI 0.970–1.836; p = 0.076). Conclusions: In the present research, hyperglycemia during pregnancy and poor oral hygiene habits during the first trimester of gestation led to a higher risk of poor oral quality of life during late pregnancy.