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Simple Summary: Chimeric antigen receptor T cell (CAR-T) therapy has demonstrated significant success in B-cell lymphoma. The combination with autologous stem cell transplantation (ASCT) further enhances the efficacy of CAR-T cell therapy, although its impact on adverse reactions remains inconclusive. This study examined 147 patients who received CAR-T alone and 145 patients who underwent ASCT combined with CAR-T for B-cell lymphoma. The combined group had a higher incidence of overall and grade 1–2 CRS, but the risk of grade 3–4 CRS and CRES was not elevated. A univariate logistic regression analysis revealed that females had a lower incidence of grade 3–4 CRS but a higher incidence of severe CRES. The involvement of the central nervous system also correlated with increased CRES occurrence. The findings suggest that combining ASCT with CAR-T does not heighten the risk of severe adverse effects post-infusion. However, further validation through multicenter, prospective clinical studies is necessary to establish CAR-T combined with ASCT as a superior treatment paradigm. (1) Background: The combination of CAR-T with ASCT has been observed to enhance the efficacy of CAR-T cell therapy. However, the impact of this combination on adverse reactions is still uncertain. (2) Methods: Between January 2019 and February 2023, 292 patients diagnosed with r/r B-cell lymphoma received either CAR-T therapy alone or in combination with ASCT at our institution. We evaluated the incidence of CRS and CRES and utilized a logistic regression model to identify factors contributing to severe CRS (grade 3–4) and CRES (grade 3–4). (3) Results: The overall incidence of CRS and CRES was 78.9% and 8.2% in 147 patients receiving CAR-T alone, and 95.9% and 15.2% in 145 patients receiving CAR-T combined with ASCT, respectively. The incidence of overall CRS (p < 0.0001) and mild CRS (grade 1–2) (p = 0.021) was elevated in the ASCT combined with CAR-T group. No significant difference was observed in severe CRS and CRES between the groups. Among the 26 cases of lymphoma involving the central nervous system (CNS), 96.2% (25/26) developed CRS (15.4% grade 3–4), and 34.6% (9/26) manifested CRES (7.7% grade 3–4). Female patients had a lower incidence of severe CRS but a higher incidence of severe CRES. Lymphomas with CNS involvement demonstrated a higher risk of CRES compared to those without central involvement. (4) Conclusions: The combination of ASCT with CAR-T demonstrated a preferable option in r/r B-cell lymphoma without an increased incidence of severe CRS and CRES. [ABSTRACT FROM AUTHOR]